Ocular Manifestations of Paediatric Inflammatory Bowel Disease: A Systematic Review and Meta-analysis

Ocular Manifestations of Paediatric Inflammatory Bowel Disease: A Systematic Review and... Abstract Background and Aims Ocular extraintestinal manifestations [O-EIMs] are known complications of Crohn’s disease [CD], ulcerative colitis [UC], and inflammatory bowel disease unclassified [IBD-U]. However, data on their prevalence in children are scarce and there are no clear recommendations on what follow-up should be offered. We aimed to review available data on O-EIMs in children. Methods In January 2018, we performed a systematic review of published English literature using PubMed and EMBASE databases and disease-specific queries. Results Fifteen studies [7467 patients] reported data on O-EIMs prevalence in children. Overall prevalence of O-EIMs was 0.62–1.82%. Uveitis was the most common O-EIM. Meta-analysis showed that children with CD are at increased risk of O-EIMs as compared with children with UC and IBD-U (odds ratio [OR] 2.70, 95% confidence interval [CI] 1.51–4.83). Five studies [357 patients] reported data on ophthalmological screening in asymptomatic children: mild asymptomatic uveitis was identified in a variable proportion of patients [1.06–23.1%], more frequently in male patients with CD and colonic involvement. No evidence of ocular complications from untreated uveitis was detected. A total of 23 case reports [24 patients] were identified. Conclusions Data on O-EIMs in children are scarce. Prevalence of O-EIMs is lower than in adults but may be underestimated because of the possibility of asymptomatic uveitis; however, the long-term significance of this condition is unknown. Children with CD may be at increased risk of O-EIMs. No recommendations on routine ophthalmological examination can be made, but a low threshold for ophthalmological referral should be maintained. Larger studies in paediatric IBD populations are needed. Ocular, extraintestinal manifestations, eye, IBD, children 1. Introduction Inflammatory bowel disease [IBD], including Crohn’s disease [CD], ulcerative colitis [UC], and IBD-unclassified [IBD-U], are chronic inflammatory disorders mainly affecting the gastrointestinal tract. They are associated with various extraintestinal manifestations [EIMs], which affect approximately 10% to 40% of patients1–3 and may potentially involve almost any organ, even before gastrointestinal symptoms appear. Ocular EIMs [O-EIMs] have been recognised since the early descriptions by Crohn,4 and are among the most common EIMs. Uveitis and episcleritis are among the most commonly reported conditions in adult patients, with a prevalence between 2% and 6% in large cohort studies.3,5,6 However, when a wider spectrum of ocular conditions is considered, a higher prevalence has been reported.6–9 O-EIMs may be associated with potentially severe outcomes. Uveitis, in particular, is associated with ocular pain, photophobia, and blurred vision, and when untreated may lead to several ocular complications, including keratopathy, cataract, glaucoma, posterior synechiae, cystoid macular oedema, and permanent vision loss. Other rarer, but potentially severe, ocular manifestations in patients with IBD include retinal vasculitis, central retinal artery/vein occlusion, retrobulbar neuritis, keratopathy, and orbital myositis. Data on O-EIMs prevalence and clinical course in children are scarce and there are no clear recommendations on which ophthalmological investigations and what follow-up should be offered—unlike other paediatric inflammatory disorders, such as juvenile idiopathic arthritis, for which an ophthalmological screening schedule has been developed.10 We aimed to review published data on the prevalence and clinical course of O-EIMs from observational studies in children with IBD, in order to better define their epidemiology and clinical characteristics, as well as possibly identifying clinical phenotypes that may be associated with a higher risk of ocular involvement. 2. Methods We performed a systematic review of O-EIMs in IBD children according to the MOOSE guidelines.11 We searched PubMed and EMBASE databases for studies published from inception to January 31, 2018, using the following queries: [1] [uveitis OR scleritis OR episcleritis OR iritis OR iridocyclitis OR ‘pars planitis’ OR choroiditis OR chorioretinitis OR retinitis OR papillitis OR ocular OR eye OR ophthalmologic OR ophthalmic OR orbital OR retinal OR optic OR dacryoadenitis OR keratopathy OR corneal OR conjunctivitis OR blepharitis OR cataract OR intra-ocular OR ‘visual acuity’ OR blindness OR uveal OR lacrimal] AND [Crohn OR ‘ulcerative colitis’ OR ‘inflammatory bowel disease’]; [2] [‘extraintestinal manifestation’ OR ‘extraintestinal manifestation’ OR ‘extraintestinal manifestations’ OR ‘extraintestinal manifestations’] AND [children OR pediatric] AND [‘Crohn’ or ‘ulcerative colitis’ OR ‘inflammatory bowel disease’]. 2.1. Data selection Two authors [GO, SN] independently reviewed search results and found a consensus on the articles to be included. Articles references were also considered for additional studies. To be analysed, studies had to report original data on O-EIMs in children with IBD. We included observational studies, as well as case reports. Limits related to age [0–18 years] and languages [English] were applied. Abstracts and unpublished studies were not included. If studies contained data from both adult and paediatric IBD patients, data from the two populations had to be clearly discernible. When articles contained potentially relevant data not fully reported, the authors were contacted by email for further information. Only in two cases were contacted authors able to provide the requested information, which were therefore included in our review, whereas the other authors declared their inability to provide complete data. 2.2. Meta-analysis Mantel-Haenszel weighting and random effects models were used. Statistical heterogeneity across studies was measured using the Cochran chi square test [p < 0.1 considered significant] and the I2 statistic. Variance was evaluated by means of tau.2 All statistical tests were two sided using an α level of 0.05. Publication bias was assessed by funnel plot. The meta-analyses were conducted with the statistical software Review Manager [RevMan] version 5.3 [The Cochrane Collaboration, 2014, Copenhagen, Denmark]. 3. Results We retrieved 1499 and 264 articles from the query one and two, respectively. We excluded 1470 and 247 articles because they did not meet inclusion criteria. Seven articles were found through both queries. Four other articles were found through the reference list of the included articles. Finally, we selected 43 articles for the analysis [Figure 1]. Figure 1. View largeDownload slide Flow chart of systematic literature search and selection process for systematic review. Figure 1. View largeDownload slide Flow chart of systematic literature search and selection process for systematic review. 3.1. Prevalence of O-EIMs in children Fifteen studies, including a total of 7467 patients, reported the prevalence of symptomatic ocular complications in children [Table 1].12–25 Substantial heterogeneity was present among studies. Timing of data collection varied, as some studies included only O-EIMs present at IBD diagnosis whereas others also considered O-EIMs appearing during follow-up. Studies also differed for O-EIMs inclusion criteria, since some authors reported data only for uveitis, whereas others also included other O-EIMs [e.g. episcleritis, papilledoema, corneal infiltrates], and other articles generically reported ‘ocular manifestations’ without further details. Finally, the methodology of O-EIMs ascertainment was poorly described or not reported in most studies, making comparative evaluation difficult to perform. Table 1. Studies reporting prevalence of O-EIMs in IBD children [ordered by population size]. No. of IBD patients O-EIMs considered Timing of data collection O-EIMs prevalence O-EIMs prevalence according to IBD type CD UC IBD-U Jose et al. 12 1649 Uveitis, papilleodema, Corneal infiltrates During follow-up [only first-appearing EIMs] 1.63% [27/1649] - - - Card et al.13 1594 Uveitis During follow-up 1.63% [26/1594] 2.07% [21/1014] 0.86% [5/580] - Castro et al.14 1576 Ocular manifestations, not better specified At diagnosis 1.07% [17/1576] 1.73% [11/635] 0.74% [6/810] 0% [0/131] Dotson et al.15 1009 Uveitis During follow-up 0.69% [7/1009] 0.82% [6/728] 0.36% [1/281] - Dimakou et al.16 483 Ocular manifestations, not better specified At diagnosis 0.62% [3/483] 0.60% [1/167] 0.37% [1/267] 2.04% [1/49] Greuter et al.17 329 Uveitis During follow-up 1.82% [6/329] 2.9% [5/173] 0.64% [1/156]a Duricova et al.18 158 Uveitis At diagnosis 1.27% [2/158] - 1.27% [2/158] - Cakir et al.19 127 Uveitis At diagnosis 1.57% [2/127] 3.4% [1/29] 1.1% [1/90] - Gower-Rousseau et al.20 113 Uveitis During follow-up 3.54% [4/113] - 3.54% [4/113] - Martinelli et al. 21 111 Uveitis During follow-up 1.80% [2/111] - 1.80% [2/111] - Saadah 22 96 Uveitis, keratitis At diagnosis 2.11% [2/96] 2.11% [2/96] - - Naviglio et al. 23 94 Uveitis During follow-up 1.06% [1/94] 2.17% [1/46] 0% [0/46] 0% [0/2] Lee et al. 24 73 Uveitis During follow-up 1.37% [1/73] 1.37% [1/73] - - Abdul Aziz 25 55 Uveitis At diagnosis 1.81% [1/55] 10% [1/10] 0% [0/34] 0% [0/11] No. of IBD patients O-EIMs considered Timing of data collection O-EIMs prevalence O-EIMs prevalence according to IBD type CD UC IBD-U Jose et al. 12 1649 Uveitis, papilleodema, Corneal infiltrates During follow-up [only first-appearing EIMs] 1.63% [27/1649] - - - Card et al.13 1594 Uveitis During follow-up 1.63% [26/1594] 2.07% [21/1014] 0.86% [5/580] - Castro et al.14 1576 Ocular manifestations, not better specified At diagnosis 1.07% [17/1576] 1.73% [11/635] 0.74% [6/810] 0% [0/131] Dotson et al.15 1009 Uveitis During follow-up 0.69% [7/1009] 0.82% [6/728] 0.36% [1/281] - Dimakou et al.16 483 Ocular manifestations, not better specified At diagnosis 0.62% [3/483] 0.60% [1/167] 0.37% [1/267] 2.04% [1/49] Greuter et al.17 329 Uveitis During follow-up 1.82% [6/329] 2.9% [5/173] 0.64% [1/156]a Duricova et al.18 158 Uveitis At diagnosis 1.27% [2/158] - 1.27% [2/158] - Cakir et al.19 127 Uveitis At diagnosis 1.57% [2/127] 3.4% [1/29] 1.1% [1/90] - Gower-Rousseau et al.20 113 Uveitis During follow-up 3.54% [4/113] - 3.54% [4/113] - Martinelli et al. 21 111 Uveitis During follow-up 1.80% [2/111] - 1.80% [2/111] - Saadah 22 96 Uveitis, keratitis At diagnosis 2.11% [2/96] 2.11% [2/96] - - Naviglio et al. 23 94 Uveitis During follow-up 1.06% [1/94] 2.17% [1/46] 0% [0/46] 0% [0/2] Lee et al. 24 73 Uveitis During follow-up 1.37% [1/73] 1.37% [1/73] - - Abdul Aziz 25 55 Uveitis At diagnosis 1.81% [1/55] 10% [1/10] 0% [0/34] 0% [0/11] IBD-U, inflammatory bowel disease unclassified; O-EIM, ocular extraintestinal manifestation; CD, Crohn’s disease; UC, ulcerative colitis. aAggregate data [UC+IBD-U]. View Large Table 1. Studies reporting prevalence of O-EIMs in IBD children [ordered by population size]. No. of IBD patients O-EIMs considered Timing of data collection O-EIMs prevalence O-EIMs prevalence according to IBD type CD UC IBD-U Jose et al. 12 1649 Uveitis, papilleodema, Corneal infiltrates During follow-up [only first-appearing EIMs] 1.63% [27/1649] - - - Card et al.13 1594 Uveitis During follow-up 1.63% [26/1594] 2.07% [21/1014] 0.86% [5/580] - Castro et al.14 1576 Ocular manifestations, not better specified At diagnosis 1.07% [17/1576] 1.73% [11/635] 0.74% [6/810] 0% [0/131] Dotson et al.15 1009 Uveitis During follow-up 0.69% [7/1009] 0.82% [6/728] 0.36% [1/281] - Dimakou et al.16 483 Ocular manifestations, not better specified At diagnosis 0.62% [3/483] 0.60% [1/167] 0.37% [1/267] 2.04% [1/49] Greuter et al.17 329 Uveitis During follow-up 1.82% [6/329] 2.9% [5/173] 0.64% [1/156]a Duricova et al.18 158 Uveitis At diagnosis 1.27% [2/158] - 1.27% [2/158] - Cakir et al.19 127 Uveitis At diagnosis 1.57% [2/127] 3.4% [1/29] 1.1% [1/90] - Gower-Rousseau et al.20 113 Uveitis During follow-up 3.54% [4/113] - 3.54% [4/113] - Martinelli et al. 21 111 Uveitis During follow-up 1.80% [2/111] - 1.80% [2/111] - Saadah 22 96 Uveitis, keratitis At diagnosis 2.11% [2/96] 2.11% [2/96] - - Naviglio et al. 23 94 Uveitis During follow-up 1.06% [1/94] 2.17% [1/46] 0% [0/46] 0% [0/2] Lee et al. 24 73 Uveitis During follow-up 1.37% [1/73] 1.37% [1/73] - - Abdul Aziz 25 55 Uveitis At diagnosis 1.81% [1/55] 10% [1/10] 0% [0/34] 0% [0/11] No. of IBD patients O-EIMs considered Timing of data collection O-EIMs prevalence O-EIMs prevalence according to IBD type CD UC IBD-U Jose et al. 12 1649 Uveitis, papilleodema, Corneal infiltrates During follow-up [only first-appearing EIMs] 1.63% [27/1649] - - - Card et al.13 1594 Uveitis During follow-up 1.63% [26/1594] 2.07% [21/1014] 0.86% [5/580] - Castro et al.14 1576 Ocular manifestations, not better specified At diagnosis 1.07% [17/1576] 1.73% [11/635] 0.74% [6/810] 0% [0/131] Dotson et al.15 1009 Uveitis During follow-up 0.69% [7/1009] 0.82% [6/728] 0.36% [1/281] - Dimakou et al.16 483 Ocular manifestations, not better specified At diagnosis 0.62% [3/483] 0.60% [1/167] 0.37% [1/267] 2.04% [1/49] Greuter et al.17 329 Uveitis During follow-up 1.82% [6/329] 2.9% [5/173] 0.64% [1/156]a Duricova et al.18 158 Uveitis At diagnosis 1.27% [2/158] - 1.27% [2/158] - Cakir et al.19 127 Uveitis At diagnosis 1.57% [2/127] 3.4% [1/29] 1.1% [1/90] - Gower-Rousseau et al.20 113 Uveitis During follow-up 3.54% [4/113] - 3.54% [4/113] - Martinelli et al. 21 111 Uveitis During follow-up 1.80% [2/111] - 1.80% [2/111] - Saadah 22 96 Uveitis, keratitis At diagnosis 2.11% [2/96] 2.11% [2/96] - - Naviglio et al. 23 94 Uveitis During follow-up 1.06% [1/94] 2.17% [1/46] 0% [0/46] 0% [0/2] Lee et al. 24 73 Uveitis During follow-up 1.37% [1/73] 1.37% [1/73] - - Abdul Aziz 25 55 Uveitis At diagnosis 1.81% [1/55] 10% [1/10] 0% [0/34] 0% [0/11] IBD-U, inflammatory bowel disease unclassified; O-EIM, ocular extraintestinal manifestation; CD, Crohn’s disease; UC, ulcerative colitis. aAggregate data [UC+IBD-U]. View Large Overall prevalence of O-EIMs in IBD at diagnosis ranged from 0.62% [3/483 patients, Dimakou et al.16] to 1.81% [1/55 patients, Abdul Aziz et al.25]. Prevalence during follow-up ranged from 0.69% [7/1009 patients, Dotson et al.15] to 1.82% [6/329 patients, Greuter et al.17]. The largest available study [Jose et al.12] reported data about the first EIM in a cohort of 1649 North-American children with IBD. Among 387 children with a first EIM, 7% [27/387] had an O-EIM; 52 and 13 out of 387 children developed also a second and a third one, respectively, yet data on these EIMs were not detailed and, when contacted authors, could not provide further information; however, an overall incidence rate for anterior uveitis of 0.18 per 100 patient-years was reported. This study was also the only one among larger studies to analyse the prevalence of different types of O-EIMs, with uveitis being the most commonly reported condition [17 patients out of 27 with O-EIMs], followed by papilledoema and corneal infiltrates [7 patients—aggregate data]. A trend towards greater prevalence of O-EIMs in children with CD emerged from several studies, yet this difference did not reach statistical significance, possibly because of the limited number of patients included in each study. We performed a meta-analysis to assess the risk of O-EIMs in children according to the different IBD diagnoses. We compared the prevalence of O-EIMs in children with CD vs children with UC and IBD-U; these two latter groups of patients were analysed together because not all the studies differentiated between them. Only studies including both categories of patients were included in the meta-analysis, to allow direct between-groups comparison. Children with CD were found to be at increased risk of O-EIMs [odds ratio 2.70, 95% CI 1.51–4.83, p = 0.0008] [Figure 2]. No significant heterogeneity was detected among studies as evaluated by Cochran’s chi square test [p = 0.96] and I2 statistic [I2 = 0%]; nevertheless, data on O-EIMs diagnosis criteria and on patients’ characteristics for each study were scarce or absent. Publication bias did not seem to be relevant as evaluated by funnel plot [data not shown], yet the number of available studies was low. Figure 2. View largeDownload slide Forest plot for prevalence of ocular extraintestinal manifestations [O-EIMs] among children with inflammatory bowel disease [IBD]. Figure 2. View largeDownload slide Forest plot for prevalence of ocular extraintestinal manifestations [O-EIMs] among children with inflammatory bowel disease [IBD]. Dotson et al.15 evaluated the association of O-EIMs with intestinal disease localisation, presence of perianal disease, and patient’s age and sex, but no significant association was found. One study [Gower-Rousseau et al.20] reported a remarkably high prevalence of uveitis during follow-up in children with UC [four of 113 patients, 3.54%]. However, this study was relatively small and was performed only in patients with UC. Greuter et al.17 also included data on timing of uveitis appearance in their population: six of 329 patients in their cohort had a diagnosis of uveitis, which occurred at a median time of approximately 7 years after IBD diagnosis, with one case preceding intestinal disease onset.17 The same study group published also a separate sub-analysis of patients from the same database [the Swiss IBD Cohort Study] evaluated at 10 years [range 108–132 months] of follow-up.26 After 10 years, age at IBD diagnosis did not appear to influence risk of uveitis, with similar incidence rates in patients with IBD diagnosis <10 years of age, <17 years of age, <40 years of age, and >40 years of age. No study did provide information about the prevalence of O-EIMs according to the patients’ ethnicity. Jose et al. included data on patients’ ethnicity, reporting no difference on the overall risk of EIMs, but no information was available for O-EIMs.12 Finally, few studies provided details about concurrent treatments: Dotson et al.15 observed a protective effect of treatment with mesalamine/sulphasalazine, infliximab, and immunomodulators on the overall risk EIMs for patients with moderate to severe disease as compared with patients who had not received these treatments; no data, however, were specifically available for O-EIMs.15 Finally, Greuter et al.17 reported the effect of treatment with anti-tumour necrosis factor [TNF] on uveitis: two patients out of three experienced uveitis improvement with treatment; however, in two patients uveitis appeared during anti-TNF treatment. 3.2. Screening for O-EIMs in children Five studies [including 357 patients] reported data on small cohorts of asymptomatic children who underwent ophthalmological screening regardless of the presence of ocular symptoms.23,27–30 Four studies [including 299 patients] included full ophthalmological evaluation [Table 2], and a fifth study [Tripathi et al.30] evaluated only ocular side effects of corticosteroid treatment. Table 2. Studies reporting full ophthalmological screening in children with IBD. No. patients Asymptomatic uveitis Cataract Overall CD UC Daum et al.27 26 23.08% [6/26] 31.58% [6/19] 0% [0/7] 0% Hofley et al.28 147 4.08% [6/147] 6.19% [6/97] 0% [0/50] 0% Rychwalski et al.29 32 12.50% [4/32] 16.67% [3/18] 7.14% [1/14] 15.63% [5/32] Naviglio et al.23 94 1.06% [1/94] 2.17% [1/46] 0% [0/46] 1.06% [1/94] Total 299 4.86% [18/299] 9.44% [17/180] 0.85% [1/117] 2.00% [6/299] No. patients Asymptomatic uveitis Cataract Overall CD UC Daum et al.27 26 23.08% [6/26] 31.58% [6/19] 0% [0/7] 0% Hofley et al.28 147 4.08% [6/147] 6.19% [6/97] 0% [0/50] 0% Rychwalski et al.29 32 12.50% [4/32] 16.67% [3/18] 7.14% [1/14] 15.63% [5/32] Naviglio et al.23 94 1.06% [1/94] 2.17% [1/46] 0% [0/46] 1.06% [1/94] Total 299 4.86% [18/299] 9.44% [17/180] 0.85% [1/117] 2.00% [6/299] IBD-U, inflammatory bowel disease unclassified; O-EIM, ocular extraintestinal manifestation; CD, Crohn’s disease; UC, ulcerative colitis View Large Table 2. Studies reporting full ophthalmological screening in children with IBD. No. patients Asymptomatic uveitis Cataract Overall CD UC Daum et al.27 26 23.08% [6/26] 31.58% [6/19] 0% [0/7] 0% Hofley et al.28 147 4.08% [6/147] 6.19% [6/97] 0% [0/50] 0% Rychwalski et al.29 32 12.50% [4/32] 16.67% [3/18] 7.14% [1/14] 15.63% [5/32] Naviglio et al.23 94 1.06% [1/94] 2.17% [1/46] 0% [0/46] 1.06% [1/94] Total 299 4.86% [18/299] 9.44% [17/180] 0.85% [1/117] 2.00% [6/299] No. patients Asymptomatic uveitis Cataract Overall CD UC Daum et al.27 26 23.08% [6/26] 31.58% [6/19] 0% [0/7] 0% Hofley et al.28 147 4.08% [6/147] 6.19% [6/97] 0% [0/50] 0% Rychwalski et al.29 32 12.50% [4/32] 16.67% [3/18] 7.14% [1/14] 15.63% [5/32] Naviglio et al.23 94 1.06% [1/94] 2.17% [1/46] 0% [0/46] 1.06% [1/94] Total 299 4.86% [18/299] 9.44% [17/180] 0.85% [1/117] 2.00% [6/299] IBD-U, inflammatory bowel disease unclassified; O-EIM, ocular extraintestinal manifestation; CD, Crohn’s disease; UC, ulcerative colitis View Large Studies reporting full ophthalmological evaluation found asymptomatic uveitis [i.e. subclinical uveitis detected only by slit lamp examination] in several children with IBD. Three studies [Daum et al., 197927; Hofley et al., 199328; Rychwalski et al., 199729] reported a prevalence of asymptomatic uveitis substantially higher than prevalence of O-EIMs from cohort studies: 4.1% [6/147 patients, Hofley et al.], 12.5% [4/32 patients, Rychwalski et al.], and 23.1% [6/26 patients, Daum et al.]. More recently, Naviglio et al.23 reported a lower prevalence [1/94 patients, 1.06%] of uveitis in a sample of paediatric patients with IBD who had undergone ophthalmological screening evaluation. In this study, only one patient was found to have asymptomatic anterior uveitis on screening slit lamp examination; the same patient also had a history of previous bilateral symptomatic [i.e. eye redness and discomfort] anterior uveitis 7 years earlier, at IBD onset. Uveitis had been treated with dexamethasone eye drops and had not recurred for the 7 years. No other patient had a history of O-EIMs diagnoses. Furthermore, no patient had ocular signs of complications from previous, unrecognised uveitis at ophthalmological evaluation. Considering combined data from these four studies, a total of 299 patients were screened [180 CD, 117 UC, and 2 IBD-U]. Asymptomatic uveitis was detected in 18/299 patients [4.86%] and was characterised as mild anterior uveitis in all patients. Asymptomatic uveitis was detected more frequently in CD [CD/UC = 17/1; prevalence in CD patients = 9.4%; prevalence in UC patients = 0.85%], adolescent [mean age 14.5 years], and male [M/F = 14/4] patients. Colonic involvement was prevalent [13 out of 14 patients for whom data are available]. Presence of HLA-B27 was reported only by Daum et al. [1/6 patients].27 Intestinal disease activity was not related to ocular inflammation [active intestinal disease in 6/12 patients with uveitis; no data available from Daum et al.]. In all cases of asymptomatic uveitis, no specific treatment was deemed necessary. Data on short-term follow-up [4–12 months] are available only for patients reported by Daum et al.27 and Naviglio et al.23: uveitis resolved in 6/7 patients overall [one patient was lost to follow-up]; the long-term outcomes were not reported. Posterior subcapsular cataract, a known adverse effect of corticosteroid treatment, was detected in six patients [five by Rychwalski et al.,29 one by Naviglio et al.,23 and in no patients from the other two studies] [overall prevalence 6/299 patients, 2.0%]. A fifth study, by Tripathi et al.,30 performed an ophthalmological evaluation targeted at ocular side effects of corticosteroid treatment.30 In all, 58 paediatric patients with IBD treated with corticosteroids, as well as 58 age-matched controls, were evaluated. Most patients [38/58] had received corticosteroid treatment for more than a year [range 1–104 months]. Posterior subcapsular cataract was detected in 12 patients [20.7%] and in none of the controls. Patients also had a significintra-ocantly higher intra-ocular pressure [15.89 +/- 4.11 mmHg vs 13.63 +/- 2.35 mmHg, p < 0.001], with 21 patients [36.2%] defined as ‘intra-ocular pressure responders’ [intra-ocular pressure ≥20 mmHg, or change ≥6 mmHg between visits, or a difference ≥6 mmHg between the two eyes]. Overall 30 patients [52%] had either cataract or abnormal intra-ocular pressure. Cataract risk was not correlated with the total dose of corticosteroids, duration of treatment, average daily dose, or number of days on higher doses, whereas increased intra-ocular pressure was correlated with average daily dose in the past 30 days. At follow-up visits, performed at 3–18 months after initial evaluation, dose-related changes in ophthalmological findings were observed. Notably, cataract regression was observed in two patients lowering the prednisone daily dose to less than 10 mg/day of prednisone. Similarly, increased ocular pressure responded to lowering of dose to less than 10 mg/day; on the other hand, an increase in corticosteroid dose was associated with abnormal intra-ocular pressure in some patients with previously normal findings. 3.3. Case reports We retrieved 23 case reports/case series including 24 children with O-EIMs [Table 3]. Reported conditions included: central retinal vein/artery occlusion,31–33 orbital myositis/orbital pseudotumour,34–40 choroidal neovascular membrane,41 nasolacrimal duct obstruction,42 dacryoadenitis,43 dry eyes syndrome,44 cataract,44 unilateral/bilateral uveitis,45–47 episcleritis,48 keratopathy/keratitis,49,50 granulomatous conjunctivitis,51 optic neuritis,52 and recurrent neuroretinitis.53 All patients presented with ocular symptoms when evaluated, including reduced visual acuity [even sudden vision loss], ocular pain/discomfort, redness, eyelid swelling, proptosis, photophobia, and diplopia. Considering all patients for whom detailed information were available, more patients were male [M/F = 14/8] and had CD [CD/UC = 18/5]. Mean age at O-EIM onset was 13 years [range 2–20 years]. Five patients were diagnosed with ophthalmological conditions before IBD onset, and in 11 patients they were present at IBD diagnosis. When O-EIMs occurred after IBD onset, latency ranged from 2 to 8 years. Complete resolution was reported in most cases of inflammatory complications [i.e. uveitis, orbital myositis/pseudotumour, neuroretinitis, and optic neuritis], but persistent visual impairment was reported in a 6-year-old boy with intermediate uveitis who had residual amblyopia despite resolution of uveitis.47 Treatment included systemic steroids in almost all reported cases; methotrexate was used in one case of orbital pseudotumour, leading to resolution.40 Vascular conditions [central retinal artery or vein occlusion, choroidal neovascular membrane] had a worse prognosis, with residual visual impairment in three out of four patients. Table 3. Case reports on ocular complications in children with IBD. 1st author, year Ocular signs and symptoms O-EIM diagnosis IBD O-EIM onset [y] IBD onset [y] Sex IBD localisation Other EIMs Therapy Outcome Symeonidis47 Low visual acuity Unilateral intermediate uveitis CD 6 6 [after 5 months] M Terminal ileum Arthritis Systemic steroids Resolved uveitis, persistent amblyopia Lapsia33 Low visual acuity Bilateral central retinal vein occlusion UC 19 17 M ND ND Enoxaparin, Bevacizumab, colectomy Improved visual acuity Vargason40 Eyelid swelling Orbital myositis CD 15 15 M Terminal ileum ND Systemic steroids methotrexate Resolved Tan39 Ocular pain and swelling Bilateral orbital pseudotumour UC 2 2 F Pancolitis Arthritis Vasculitis NSAIDs Resolved Thomas41 Low visual acuity Unilateral choroidal neovascular membrane CD 13 15 M ND ND Intravitreal bevacizumab Stabilised Fasci-Spurio49 Low visual acuity Bilateral rosacea-like keratopathy CD 16 16 M Pancolitis EN Acne rosacea Anti-TNF discontinuation Resolved Falavarjani32 Low visual acuity Unilateral central retinal artery occlusion CD 9 5 M ND ND None Optic nerve atrophy Greninger42 Epiphora, enlarged lacrimal sacs Bilateral granulomatous dacryocystitis CD 16 13 M Ileocolonic Granulomatous cheilitis External dacryocysto-rhinostomy ND Barabino52 Bilateral visual loss Optic neuritis CD 11 11 M Stomach, duodenum, colon ND Systemic steroids Resolved Paroli45 Bilateral ocular pain redness Bilateral anterior uveitis, optic disc oedema CD 4 12 M ND EN, arthritis aphthous stomatitis Topical and systemic steroids Resolved Vayalambrone31 Low visual acuity Nonischaemic central retinal vein occlusion UC 16 16 F ND ND ND Improved visual acuity Girardin46 Low visual acuity Photophobia Bilateral anterior uveitis CD 17 17 M Stomach, duodenum, ileocolonic ND Topical steroids Resolved Rafiei43 Bilateral upper eyelid swelling Bilateral dacryoadenitis CD 10 10 F Ileum, colon Arthralgia, aphthous stomatitis Systemic steroids Resolved Mrugacz44 Low visual acuity, ocular pain, redness, photophobia, foreign body sensation Dry eyes, bilateral posterior subcapsular cataract CD 11 4 F ND ND Hyaluronan eye drops [tears substitute] Dry eye syndrome resolved; stable cataract Shoari53 Low visual acuity, ocular pain Recurrent neuroretinitis UC 14 17 M Pancolitis ND Systemic steroids Improved visual acuity Read48 ND Episcleritis ND 16 ND M ND ND ND ND Durno38 Proptosis, periorbital swelling Orbital myositis CD 12 13 F Stomach, duodenum ileocolonic ND 5-ASA Resolved Squires37 Orbital pain diplopia Unilateral orbital myositis CD 20 12 M Ileocolonic ND Systemic steroids Resolved Seo50 ND Keratitis CD ND ND ND ND ND ND ND ND Chronic conjunctivitis UC ND ND ND ND ND ND ND Blase51 Bilateral eye redness Granulomatous conjunctivitis CD 13 13 M Rectum ND Systemic steroids Resolved Weinstein36 Ocular pain, diplopia, ptosis Unilateral orbital pseudotumour CD 17 17 F Colon ND Systemic steroids Resolved Camfield35 Ocular pain, photophobia Bilateral orbital pseudotumour CD 15 15 F Terminal ileum ND Systemic steroids Resolved Young34 Ocular pain, proptosis, diplopia Bilateral orbital pseudotumour CD 14 14 F Terminal ileum ND Systemic steroids, bowel resection Resolved 1st author, year Ocular signs and symptoms O-EIM diagnosis IBD O-EIM onset [y] IBD onset [y] Sex IBD localisation Other EIMs Therapy Outcome Symeonidis47 Low visual acuity Unilateral intermediate uveitis CD 6 6 [after 5 months] M Terminal ileum Arthritis Systemic steroids Resolved uveitis, persistent amblyopia Lapsia33 Low visual acuity Bilateral central retinal vein occlusion UC 19 17 M ND ND Enoxaparin, Bevacizumab, colectomy Improved visual acuity Vargason40 Eyelid swelling Orbital myositis CD 15 15 M Terminal ileum ND Systemic steroids methotrexate Resolved Tan39 Ocular pain and swelling Bilateral orbital pseudotumour UC 2 2 F Pancolitis Arthritis Vasculitis NSAIDs Resolved Thomas41 Low visual acuity Unilateral choroidal neovascular membrane CD 13 15 M ND ND Intravitreal bevacizumab Stabilised Fasci-Spurio49 Low visual acuity Bilateral rosacea-like keratopathy CD 16 16 M Pancolitis EN Acne rosacea Anti-TNF discontinuation Resolved Falavarjani32 Low visual acuity Unilateral central retinal artery occlusion CD 9 5 M ND ND None Optic nerve atrophy Greninger42 Epiphora, enlarged lacrimal sacs Bilateral granulomatous dacryocystitis CD 16 13 M Ileocolonic Granulomatous cheilitis External dacryocysto-rhinostomy ND Barabino52 Bilateral visual loss Optic neuritis CD 11 11 M Stomach, duodenum, colon ND Systemic steroids Resolved Paroli45 Bilateral ocular pain redness Bilateral anterior uveitis, optic disc oedema CD 4 12 M ND EN, arthritis aphthous stomatitis Topical and systemic steroids Resolved Vayalambrone31 Low visual acuity Nonischaemic central retinal vein occlusion UC 16 16 F ND ND ND Improved visual acuity Girardin46 Low visual acuity Photophobia Bilateral anterior uveitis CD 17 17 M Stomach, duodenum, ileocolonic ND Topical steroids Resolved Rafiei43 Bilateral upper eyelid swelling Bilateral dacryoadenitis CD 10 10 F Ileum, colon Arthralgia, aphthous stomatitis Systemic steroids Resolved Mrugacz44 Low visual acuity, ocular pain, redness, photophobia, foreign body sensation Dry eyes, bilateral posterior subcapsular cataract CD 11 4 F ND ND Hyaluronan eye drops [tears substitute] Dry eye syndrome resolved; stable cataract Shoari53 Low visual acuity, ocular pain Recurrent neuroretinitis UC 14 17 M Pancolitis ND Systemic steroids Improved visual acuity Read48 ND Episcleritis ND 16 ND M ND ND ND ND Durno38 Proptosis, periorbital swelling Orbital myositis CD 12 13 F Stomach, duodenum ileocolonic ND 5-ASA Resolved Squires37 Orbital pain diplopia Unilateral orbital myositis CD 20 12 M Ileocolonic ND Systemic steroids Resolved Seo50 ND Keratitis CD ND ND ND ND ND ND ND ND Chronic conjunctivitis UC ND ND ND ND ND ND ND Blase51 Bilateral eye redness Granulomatous conjunctivitis CD 13 13 M Rectum ND Systemic steroids Resolved Weinstein36 Ocular pain, diplopia, ptosis Unilateral orbital pseudotumour CD 17 17 F Colon ND Systemic steroids Resolved Camfield35 Ocular pain, photophobia Bilateral orbital pseudotumour CD 15 15 F Terminal ileum ND Systemic steroids Resolved Young34 Ocular pain, proptosis, diplopia Bilateral orbital pseudotumour CD 14 14 F Terminal ileum ND Systemic steroids, bowel resection Resolved IBD-U, inflammatory bowel disease unclassified; O-EIM, ocular extraintestinal manifestation; CD, Crohn’s disease; UC, ulcerative colitis; y, years; M, male; F female; ND, no data; NSAID, non-steroidal anti-inflammatory drug, EN, erythema nodosum, 5-ASA, mesalamine. View Large Table 3. Case reports on ocular complications in children with IBD. 1st author, year Ocular signs and symptoms O-EIM diagnosis IBD O-EIM onset [y] IBD onset [y] Sex IBD localisation Other EIMs Therapy Outcome Symeonidis47 Low visual acuity Unilateral intermediate uveitis CD 6 6 [after 5 months] M Terminal ileum Arthritis Systemic steroids Resolved uveitis, persistent amblyopia Lapsia33 Low visual acuity Bilateral central retinal vein occlusion UC 19 17 M ND ND Enoxaparin, Bevacizumab, colectomy Improved visual acuity Vargason40 Eyelid swelling Orbital myositis CD 15 15 M Terminal ileum ND Systemic steroids methotrexate Resolved Tan39 Ocular pain and swelling Bilateral orbital pseudotumour UC 2 2 F Pancolitis Arthritis Vasculitis NSAIDs Resolved Thomas41 Low visual acuity Unilateral choroidal neovascular membrane CD 13 15 M ND ND Intravitreal bevacizumab Stabilised Fasci-Spurio49 Low visual acuity Bilateral rosacea-like keratopathy CD 16 16 M Pancolitis EN Acne rosacea Anti-TNF discontinuation Resolved Falavarjani32 Low visual acuity Unilateral central retinal artery occlusion CD 9 5 M ND ND None Optic nerve atrophy Greninger42 Epiphora, enlarged lacrimal sacs Bilateral granulomatous dacryocystitis CD 16 13 M Ileocolonic Granulomatous cheilitis External dacryocysto-rhinostomy ND Barabino52 Bilateral visual loss Optic neuritis CD 11 11 M Stomach, duodenum, colon ND Systemic steroids Resolved Paroli45 Bilateral ocular pain redness Bilateral anterior uveitis, optic disc oedema CD 4 12 M ND EN, arthritis aphthous stomatitis Topical and systemic steroids Resolved Vayalambrone31 Low visual acuity Nonischaemic central retinal vein occlusion UC 16 16 F ND ND ND Improved visual acuity Girardin46 Low visual acuity Photophobia Bilateral anterior uveitis CD 17 17 M Stomach, duodenum, ileocolonic ND Topical steroids Resolved Rafiei43 Bilateral upper eyelid swelling Bilateral dacryoadenitis CD 10 10 F Ileum, colon Arthralgia, aphthous stomatitis Systemic steroids Resolved Mrugacz44 Low visual acuity, ocular pain, redness, photophobia, foreign body sensation Dry eyes, bilateral posterior subcapsular cataract CD 11 4 F ND ND Hyaluronan eye drops [tears substitute] Dry eye syndrome resolved; stable cataract Shoari53 Low visual acuity, ocular pain Recurrent neuroretinitis UC 14 17 M Pancolitis ND Systemic steroids Improved visual acuity Read48 ND Episcleritis ND 16 ND M ND ND ND ND Durno38 Proptosis, periorbital swelling Orbital myositis CD 12 13 F Stomach, duodenum ileocolonic ND 5-ASA Resolved Squires37 Orbital pain diplopia Unilateral orbital myositis CD 20 12 M Ileocolonic ND Systemic steroids Resolved Seo50 ND Keratitis CD ND ND ND ND ND ND ND ND Chronic conjunctivitis UC ND ND ND ND ND ND ND Blase51 Bilateral eye redness Granulomatous conjunctivitis CD 13 13 M Rectum ND Systemic steroids Resolved Weinstein36 Ocular pain, diplopia, ptosis Unilateral orbital pseudotumour CD 17 17 F Colon ND Systemic steroids Resolved Camfield35 Ocular pain, photophobia Bilateral orbital pseudotumour CD 15 15 F Terminal ileum ND Systemic steroids Resolved Young34 Ocular pain, proptosis, diplopia Bilateral orbital pseudotumour CD 14 14 F Terminal ileum ND Systemic steroids, bowel resection Resolved 1st author, year Ocular signs and symptoms O-EIM diagnosis IBD O-EIM onset [y] IBD onset [y] Sex IBD localisation Other EIMs Therapy Outcome Symeonidis47 Low visual acuity Unilateral intermediate uveitis CD 6 6 [after 5 months] M Terminal ileum Arthritis Systemic steroids Resolved uveitis, persistent amblyopia Lapsia33 Low visual acuity Bilateral central retinal vein occlusion UC 19 17 M ND ND Enoxaparin, Bevacizumab, colectomy Improved visual acuity Vargason40 Eyelid swelling Orbital myositis CD 15 15 M Terminal ileum ND Systemic steroids methotrexate Resolved Tan39 Ocular pain and swelling Bilateral orbital pseudotumour UC 2 2 F Pancolitis Arthritis Vasculitis NSAIDs Resolved Thomas41 Low visual acuity Unilateral choroidal neovascular membrane CD 13 15 M ND ND Intravitreal bevacizumab Stabilised Fasci-Spurio49 Low visual acuity Bilateral rosacea-like keratopathy CD 16 16 M Pancolitis EN Acne rosacea Anti-TNF discontinuation Resolved Falavarjani32 Low visual acuity Unilateral central retinal artery occlusion CD 9 5 M ND ND None Optic nerve atrophy Greninger42 Epiphora, enlarged lacrimal sacs Bilateral granulomatous dacryocystitis CD 16 13 M Ileocolonic Granulomatous cheilitis External dacryocysto-rhinostomy ND Barabino52 Bilateral visual loss Optic neuritis CD 11 11 M Stomach, duodenum, colon ND Systemic steroids Resolved Paroli45 Bilateral ocular pain redness Bilateral anterior uveitis, optic disc oedema CD 4 12 M ND EN, arthritis aphthous stomatitis Topical and systemic steroids Resolved Vayalambrone31 Low visual acuity Nonischaemic central retinal vein occlusion UC 16 16 F ND ND ND Improved visual acuity Girardin46 Low visual acuity Photophobia Bilateral anterior uveitis CD 17 17 M Stomach, duodenum, ileocolonic ND Topical steroids Resolved Rafiei43 Bilateral upper eyelid swelling Bilateral dacryoadenitis CD 10 10 F Ileum, colon Arthralgia, aphthous stomatitis Systemic steroids Resolved Mrugacz44 Low visual acuity, ocular pain, redness, photophobia, foreign body sensation Dry eyes, bilateral posterior subcapsular cataract CD 11 4 F ND ND Hyaluronan eye drops [tears substitute] Dry eye syndrome resolved; stable cataract Shoari53 Low visual acuity, ocular pain Recurrent neuroretinitis UC 14 17 M Pancolitis ND Systemic steroids Improved visual acuity Read48 ND Episcleritis ND 16 ND M ND ND ND ND Durno38 Proptosis, periorbital swelling Orbital myositis CD 12 13 F Stomach, duodenum ileocolonic ND 5-ASA Resolved Squires37 Orbital pain diplopia Unilateral orbital myositis CD 20 12 M Ileocolonic ND Systemic steroids Resolved Seo50 ND Keratitis CD ND ND ND ND ND ND ND ND Chronic conjunctivitis UC ND ND ND ND ND ND ND Blase51 Bilateral eye redness Granulomatous conjunctivitis CD 13 13 M Rectum ND Systemic steroids Resolved Weinstein36 Ocular pain, diplopia, ptosis Unilateral orbital pseudotumour CD 17 17 F Colon ND Systemic steroids Resolved Camfield35 Ocular pain, photophobia Bilateral orbital pseudotumour CD 15 15 F Terminal ileum ND Systemic steroids Resolved Young34 Ocular pain, proptosis, diplopia Bilateral orbital pseudotumour CD 14 14 F Terminal ileum ND Systemic steroids, bowel resection Resolved IBD-U, inflammatory bowel disease unclassified; O-EIM, ocular extraintestinal manifestation; CD, Crohn’s disease; UC, ulcerative colitis; y, years; M, male; F female; ND, no data; NSAID, non-steroidal anti-inflammatory drug, EN, erythema nodosum, 5-ASA, mesalamine. View Large 4. Discussion Data on ocular involvement in children with IBD are scarce and fragmented. Substantial heterogeneity among studies and several methodological issues currently limit the complete evaluation of this topic. Among cohort studies reporting prevalence of O-EIMs in children with IBD, inclusion criteria for O-EIMs were, in fact, highly variable, with some authors focusing only on selected conditions [e.g. uveitis] and others reporting the presence of ‘ocular manifestations’ without further specification. Furthermore, criteria for the diagnosis of O-EIMs are not fully defined in most studies. Notwithstanding these limitations, data from cohort studies indicate a lower prevalence of ocular involvement in children [0.6–1.8%] than in adults [2–6%]. Data on different types of O-EIMs are even scarcer, with only one report [Jose et al.12] showing different prevalence for selected ocular conditions [uveitis, papilledoema, corneal infiltrates]. According to this study, uveitis represents the most common O-EIM in children with IBD. Subtype and localisation of uveitis were not indicated, yet in adult patients anterior uveitis [i.e. iritis/iridocyclitis] is predominant.54 Data on prevalence of other O-EIMs, such as episcleritis/scleritis or rarer conditions such as orbital myositis, are not available, and only data from case reports are presented. O-EIMs can affect both CD and UC patients, yet our meta-analysis showed that children with CD are at increased risk of O-EIMs as compared withchildren with other paediatric IBD, with an odds ratio of 2.70. No significant study heterogeneity was detected yet, given the paucity of information available, we had to consider together in the analysis studies on EIMs at diagnosis and during the follow-up. Nevertheless, the evaluated outcome [prevalence of O-EIMs] was uniform, and there are no data from either paediatric or adult studies suggesting that timing of data collection may bias prevalence among different IBD subtypes [CD vs UC vs IBD-U]. Hence we can assume that including both types of studies [at diagnosis vs during follow up] did not affect the relative risk analysis. In adult patients, O-EIMs are often considered to be more frequent in CD as compared with UC55; however, data from studies on adult patients are conflicting, with only some studies reporting a significantly increased prevalence of O-EIMs in CD patients, whereas in others the difference appears to be non-significant.1,3,56,57 Data on timing of O-EIMs in children are also scarce. Greuter et al.17 reported a median time of 7 years after IBD diagnosis for uveitis onset, although substantial variability was observed. Occurrence of O-EIMs before gastrointestinal symptoms onset is also possible, even though in a minority of patients; O-EIMs that have been reported to precede intestinal disease include uveitis and orbital myositis. Results from the largest study [Jose et al., 200912] indicate that the prevalence of uveitis increases with time [incidence rate: 0.18 cases per 100 patient-years]. Herzog et al.26 reported no difference for uveitis rates according to age at IBD diagnosis when patients were evaluated after 10 years, possibly indicating that age at IBD onset does not influence uveitis risk per se. Very little data are available also for correlation of O-EIMs with intestinal disease activity. Although uveitis is classically considered to be unrelated to intestinal disease activity, some studies on adult patients actually found a significant correlation with disease activity in patients with CD [but not those with UC].1 Few studies specified concurrent treatments in IBD patients, which may possibly have an effect on the risk of O-EIMs during follow-up. Dotson et al.15 reported a protective effect of immunomodulators and anti-TNF on the overall risk of EIMs in their cohort, yet no data were available for O-EIMs. Systemic immunomodulatory treatments could possibly reduce the risk of inflammatory O-EIMs, but this relationship may not be straightforward. In fact, Greuter et al.17 reported a good response of uveitis to anti-TNF antibodies in two out of three patients, yet the same authors detected uveitis during anti-TNF treatment in two other patients. We did not find evidence of a difference in prevalence of O-EIMs according to patients’ ethnicity. No study provided information on patients’ ethnicity as related to O-EIMs, yet among prevalence studies several world regions were actually included [North America, Western Europe, Turkey, Saudi Arabia, South Korea] and no difference in overall prevalence was observed. Jose et al.12 reported no significant association for patients’ ethnicity with overall EIMs prevalence, but no specific data were available for O-EIMS. Another study, by Eidelwein et al., compared EIMs prevalence between White and African American children in North America.58 This study, however, could not be included in the prevalence analysis because it did not show exact figures of the condition, stating only that uveitis prevalence was ‘less than 3%’ in both groups of patients. Contacted authors also could not provide further information. Nonetheless, no difference in overall EIMs prevalence was reported. Similarly, White et al. found no difference in overall EIMs prevalence in African American children with IBD as compared with other ethnic groups; however, subanalysis of different types of EIMs was not performed, nor could contacted authors provide further information.59 Remarkably, data from adult patients seem to suggest that prevalence of uveitis may be higher in African American CD patients as compared with other ethnic groups.60–62 The recognition of subclinical uveitis by slit lamp examination in screening evaluation in small samples of asymptomatic children with IBD raises concerns about under-diagnosis of a potentially invalidating condition. Three studies [Daum et al., 197927; Hofley et al. 1993;28 Rychwalski et al. 199729] showed a significantly increased prevalence of subclinical uveitis [4.1–23.1%] compared with that reported in cohort populations. It may be worth noting that these studies were performed more than 20 years ago [between 1979 and 1997], before the introduction of biologic anti-tumour necrosis factor alpha agents and the wider use of immune modulators, which allow better control of both gastrointestinal manifestations and EIMs.63,64 The more recent report by Naviglio et al.,23 while confirming the existence of subclinical uveitis in children with IBD, indicated a lower prevalence [1.06%], in line with the prevalence from cohort studies. In all these studies, asymptomatic uveitis was anterior, confirming this as the most common type of uveitis associated with IBD in children, even though other types of uveitis [e.g. intermediate uveitis] are also possible.47 Asymptomatic uveitis did not seem to correlate with intestinal disease activity. Interestingly, some clinical characteristics recurred among patients with asymptomatic uveitis: they were more commonly adolescent males with CD and with colonic involvement [13/14 patients]. This may confirm that CD patients are at increased risk of O-EIMs. Recent data have suggested that eye-specific autoreactive T cells may be activated in the gut from an antigen-dependent cross-reaction on commensal microbiota.65 Abnormal gut permeability in CD and increased density of microbiota in the colon could explain the increased risk of O-EIMs in these patients. However, the low number of cases does not allow us to draw a general conclusion nor to identify other significant characteristics. Clinical implications of asymptomatic uveitis are unclear. In fact, most cases were diagnosed as mild uveitis, and both Daum et al.27 and Naviglio et al.23 reported spontaneous resolution of ocular inflammation without specific treatments, suggesting that asymptomatic uveitis in children with IBD may be transient and self-limiting. Remarkably, no studies detected evidence of ocular complications from previous unrecognised uveitis, suggesting that this type of ocular manifestation may not be aggressive nor lead to complications, at least in children with IBD. This is in sharp contrast with asymptomatic uveitis associated with other paediatric chronic inflammatory disorders, such as juvenile idiopathic arthritis-associated uveitis, which has a high potential for ocular complications and visual impairment.66 Nevertheless, the natural history of asymptomatic uveitis in IBD is poorly known, and therefore definitive conclusions cannot be drawn. Notably, several treatments used in IBD are also effective for uveitis, and thus uveitis may also benefit from systemic treatments used to control intestinal disease. New studies are needed to outline specific phenotype risk and orientate proper follow-up for these patients. Iatrogenic ocular complications, mainly corticosteroid-induced posterior subcapsular cataract and increase of intra-ocular pressure, should also always be considered in children with IBD receiving corticosteroids. Available data on this complication come mostly from the case-control study by Tripathi et al.30 The majority of children [52%] developed either cataract or alteration of intra-ocular pressure; however, this study was performed mainly on children receiving long-term corticosteroid treatment, an eventuality that has now become less frequent, as corticosteroids are considered more as a ‘bridge therapy’. There are few data in medical literature defining timing and dose-related risk of corticosteroid-induced ocular complications in children. It is now well recognised that there is a high inter-individual variability in sensitivity to ocular adverse effects of corticosteroids, with some patients free of ocular complications after years of corticosteroid treatment, whereas in others they may develop rapidly [even as soon as after 2 weeks of treatment].67 Data from adult patients seem to indicate that the overall risk is dose- and time-related, even though a ‘safe dose’ does not seem to exist.68 Notably, corticosteroid-induced complications, especially increased intra-ocular pressure, did respond to dose lowering to less than 10 mg/day of prednisone in the study by Tripathi et al.,30 yet we have not enough data to consider this as a ‘safe’ dose. Therefore, at present, a precise threshold for corticosteroid dose or treatment duration to guide ophthalmological evaluation cannot be clearly defined. In the study by Tripathi et al.,30 the risk of cataract was not correlated to treatment duration or steroid dose, whereas the risk of abnormal intra-ocular pressure was associated to the average dose in the previous 30 days. It may be possible therefore to consider that this is an adequate timing for alterations of intra-ocular pressure to develop. Thus it could be reasonable to suggest that in children in whom systemic corticosteroids are considered for longer periods of time and not as a ‘bridge therapy’ [i.e. in whom tapering and suspension are not programmed after 1 month] an ophthalmological evaluation, including intra-ocular pressure measurement, should be considered after 1 month of therapy. Timing for subsequent evaluations should be decided by the referral ophthalmologist, as there are no data to guide patient management. It is noteworthy that in the study by Tripathi et al.,30 some patients with a previously normal ophthalmological evaluation developed complications after a significant increase in their daily corticosteroid dose, so this should also be taken in consideration in guiding follow-up. All these recommendations are based on low/moderate quality evidence [one case-control study], and therefore their strength should be considered as weak. Patients on very long-term corticosteroid treatment [i.e. treatment continuing for several months/years], however, are at high risk of ocular complications and a strict ocular follow-up should be offered. Available case reports of O-EIMs define a wide array of ocular conditions that have been reported in children with IBD. However, for some of them it is currently not possible to determine whether they were simply coincidental, though similar manifestations have been reported in adult patients. Presenting symptoms varied widely, from mild ocular redness or discomfort to complete loss of vision, highlighting the need not to underestimate ocular complaints in these patients. Reported O-EIMs can be roughly classified into inflammatory and vascular conditions. The first group includes uveitis, episcleritis, orbital myositis/pseudotumour, dacryoadenitis, and optic neuritis. Orbital pseudotumour, which identifies any inflammatory enlargement of intraorbital structural elements,69 despite being a rare condition, was one of the most commonly reported O-EIMs in case reports. Although the clinical manifestations may vary widely, depending on the structures affected, they often included ocular/orbital pain, diplopia, ophthalmoplegia, proptosis, eyelid swelling, and reduced visual acuity. Almost all cases involving an inflammatory O-EIM resolved with treatment, which usually included systemic corticosteroids. Among vascular conditions, we identified reports on retinal artery or vein occlusion and choroidal neovascular membrane; these complications may also share an inflammatory pathogenesis, possibly due to retinal vasculitis, which has been associated with IBD in adults.70 In most cases, vascular conditions resulted in some residual visual impairment despite treatment. Notably, also among case reports there was a preponderance of children with CD [CD/UC = 18/5], thus possibly confirming a greater incidence of O-EIMs in CD patients. In conclusion, available data indicate that prevalence of O-EIMs in children is lower than in adult patients, yet children with CD seem to be at increased risk as compared with other groups of patients. Prevalence of O-EIMs in children may be underestimated in consideration of the possibility of asymptomatic uveitis, which has not been described in adults.71 The significance of this condition, however, is unclear, as all reported cases were mild and self-limiting, with no evidence of ocular complications from underdiagnosis. Nevertheless, data on natural history of this manifestation and long-term follow-up are lacking. It has been recently suggested that annual screening eye examination should be considered in all children with IBD72; however, this is often not performed in clinical practice, nor it is possible to define the cost-benefit ratio of such an approach. Currently, the paucity of data on O-EIMs in children does not allow us to draw clear conclusions on which ophthalmological follow-up should be provided. An option may be to perform ophthalmological evaluation at IBD diagnosis in order to have a baseline reference, but we cannot provide any evidence for this suggestion. On the other hand, we recommend that a low threshold for ophthalmological referral should be maintained in all children with IBD, both at the diagnosis and during follow-up. Available data, in fact, show that most children with O-EIMs presented some ocular signs or symptoms, and therefore ocular complaints should never be dismissed; both health care providers and patients/care givers should be instructed about the increased risk of ocular complications in children with IBD. Since available data indicate a higher incidence of O-EIMs in children with CD, especially if colonic involvement is present, this subset of patients may be considered at higher risk of O-EIMs in clinical practice, but further studies on larger groups of patients are needed. Finally, patients receiving systemic corticosteroids for more than brief periods may probably benefit from ophthalmological evaluations, including intra-ocular pressure measurement. A strict follow-up should be offered in patients receiving long-term corticosteroid treatment, as these children are at increased risk for iatrogenic ocular complications. Funding No funding was received for this work. Conflict of Interest All authors declare no conflict of interests. Author Contributions GO and SN performed literature search and review, wrote the manuscript, and critically revised it. SS, AS, SM, and AV designed the study and critically reviewed the manuscript. All authors approved the manuscript as submitted. References 1. Vavricka SR , Brun L , Ballabeni P , et al. Frequency and risk factors for extraintestinal manifestations in the Swiss inflammatory bowel disease cohort . Am J Gastroenterol 2011 ; 106 : 110 – 9 . Google Scholar CrossRef Search ADS PubMed 2. Isene R , Bernklev T , Høie O , et al. ; EC-IBD Study Group . Extraintestinal manifestations in Crohn’s disease and ulcerative colitis: results from a prospective, population-based European inception cohort . Scand J Gastroenterol 2015 ; 50 : 300 – 5 . Google Scholar CrossRef Search ADS PubMed 3. Karmiris K , Avgerinos A , Tavernaraki A , et al. Prevalence and characteristics of extraintestinal manifestations in a large cohort of Greek patients with inflammatory bowel disease . J Crohns Colitis 2016 ; 10 : 429 – 36 . Google Scholar CrossRef Search ADS PubMed 4. Crohn BB . Ocular lesions complicating ulcerative colitis . Am J Med Sci 1925 ; 169 : 260 – 7 . 5. Hopkins DJ , Horan E , Burton IL , Clamp SE , de Dombal FT , Goligher JC . Ocular disorders in a series of 332 patients with Crohn’s disease . Br J Ophthalmol 1974 ; 58 : 732 – 7 . Google Scholar CrossRef Search ADS PubMed 6. Cury DB , Moss AC . Ocular manifestations in a community-based cohort of patients with inflammatory bowel disease . Inflamm Bowel Dis 2010 ; 16 : 1393 – 6 . Google Scholar CrossRef Search ADS PubMed 7. Yilmaz S , Aydemir E , Maden A , Unsal B . The prevalence of ocular involvement in patients with inflammatory bowel disease . Int J Colorectal Dis 2007 ; 22 : 1027 – 30 . Google Scholar CrossRef Search ADS PubMed 8. Taleban S , Li D , Targan SR , et al. Ocular manifestations in inflammatory bowel disease are associated with other extraintestinal manifestations, gender, and genes implicated in other immune-related traits . J Crohns Colitis 2016 ; 10 : 43 – 9 . Google Scholar CrossRef Search ADS PubMed 9. Felekis T , Katsanos K , Kitsanou M , et al. Spectrum and frequency of ophthalmologic manifestations in patients with inflammatory bowel disease: a prospective single-center study . Inflamm Bowel Dis 2009 ; 15 : 29 – 34 . Google Scholar CrossRef Search ADS PubMed 10. Cassidy J , Kivlin J , Lindsley C , Nocton J ; Section on Rheumatology; Section on Ophthalmology . Ophthalmologic examinations in children with juvenile rheumatoid arthritis . Pediatrics 2006 ; 117 : 1843 – 5 . Google Scholar CrossRef Search ADS PubMed 11. Stroup DF , Berlin JA , Morton SC , et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology [MOOSE] group . JAMA 2000 ; 283 : 2008 – 12 . Google Scholar CrossRef Search ADS PubMed 12. Jose FA , Garnett EA , Vittinghoff E , et al. Development of extraintestinal manifestations in pediatric patients with inflammatory bowel disease . Inflamm Bowel Dis 2009 ; 15 : 63 – 8 . Google Scholar CrossRef Search ADS PubMed 13. Card TR , Langan SM , Chu TP . Extra-gastrointestinal manifestations of inflammatory bowel disease may be less common than previously reported . Dig Dis Sci 2016 ; 61 : 2619 – 26 . Google Scholar CrossRef Search ADS PubMed 14. Castro M , Papadatou B , Baldassare M , et al. Inflammatory bowel disease in children and adolescents in Italy: data from the pediatric national IBD register [1996–2003] . Inflamm Bowel Dis 2008 ; 14 : 1246 – 52 . Google Scholar CrossRef Search ADS PubMed 15. Dotson JL , Hyams JS , Markowitz J , et al. Extraintestinal manifestations of pediatric inflammatory bowel disease and their relation to disease type and severity . J Pediatr Gastroenterol Nutr 2010 ; 51 : 140 – 5 . Google Scholar CrossRef Search ADS PubMed 16. Dimakou K , Pachoula I , Panayotou I , et al. Pediatric inflammatory bowel disease in Greece: 30-years experience of a single center . Ann Gastroenterol 2015 ; 28 : 81 – 6 . Google Scholar PubMed 17. Greuter T , Bertoldo F , Rechner R , et al. ; Swiss IBD Cohort Study Group . Extraintestinal manifestations of pediatric inflammatory bowel disease: prevalence, presentation, and anti-TNF treatment . J Pediatr Gastroenterol Nutr 2017 ; 65 : 200 – 6 . Google Scholar CrossRef Search ADS PubMed 18. Duricova D , Leroyer A , Savoye G , et al. Extra-intestinal manifestations at diagnosis in paediatric- and elderly-onset ulcerative colitis are associated with a more severe disease outcome: a population-based study . J Crohns Colitis 2017 ; 11 : 1326 – 34 . Google Scholar CrossRef Search ADS PubMed 19. Cakir M , Unal F , Dinler G , et al. Inflammatory bowel disease in Turkish children . World J Pediatr 2015 ; 11 : 331 – 7 . Google Scholar CrossRef Search ADS PubMed 20. Gower-Rousseau C , Dauchet L , Vernier-Massouille G , et al. The natural history of pediatric ulcerative colitis: a population-based cohort study . Am J Gastroenterol 2009 ; 104 : 2080 – 8 . Google Scholar CrossRef Search ADS PubMed 21. Martinelli M , Giugliano FP , Russo M , et al. The changing face of pediatric ulcerative colitis . J Pediatr Gastroenterol Nutr 2017 : 1 . Doi: 10.1097/MPG.0000000000001833 . [Epub ahead of print.] 22. Saadah OI . Childhood onset of Crohn disease: experience from a university teaching hospital in Saudi Arabia . Ann Saudi Med 2012 ; 32 : 596 – 602 . Google Scholar CrossRef Search ADS PubMed 23. Naviglio S , Parentin F , Nider S , Rassu N , Martelossi S , Ventura A . Ocular involvement in children with inflammatory bowel disease . Inflamm Bowel Dis 2017 ; 23 : 986 – 90 . Google Scholar CrossRef Search ADS PubMed 24. Lee YA , Chun P , Hwang EH , Mun SW , Lee YJ , Park JH . Clinical features and extraintestinal manifestations of crohn disease in children . Pediatr Gastroenterol Hepatol Nutr 2016 ; 19 : 236 – 42 . Google Scholar CrossRef Search ADS PubMed 25. Aziz DA , Moin M , Majeed A , Sadiq K , Biloo AG . Paediatric inflammatory bowel disease: clinical presentation and disease location . Pak J Med Sci 2017 ; 33 : 793 – 7 . Google Scholar PubMed 26. Herzog D , Fournier N , Buehr P , et al. Age at disease onset of inflammatory bowel disease is associated with later extraintestinal manifestations and complications . Eur J Gastroenterol Hepatol 2018 : 1 . Doi: 10.1097/MEG.0000000000001072 . 27. Daum F , Gould HB , Gold D , et al. Asymptomatic transient uveitis in children with inflammatory bowel disease . Am J Dis Child 1979 ; 133 : 170 – 1 . Google Scholar PubMed 28. Hofley P , Roarty J , McGinnity G , et al. Asymptomatic uveitis in children with chronic inflammatory bowel diseases . J Pediatr Gastroenterol Nutr 1993 ; 17 : 397 – 400 . Google Scholar CrossRef Search ADS PubMed 29. Rychwalski PJ , Cruz OA , Alanis-Lambreton G , Foy TM , Kane RE . Asymptomatic uveitis in young people with inflammatory bowel disease . J AAPOS 1997 ; 1 : 111 – 4 . Google Scholar CrossRef Search ADS PubMed 30. Tripathi RC , Kipp MA , Tripathi BJ , et al. Ocular toxicity of prednisone in pediatric patients with inflammatory bowel disease . Lens Eye Toxic Res 1992 ; 9 : 469 – 82 . Google Scholar PubMed 31. Vayalambrone D , Ivanova T , Misra A . Nonischemic central retinal vein occlusion in an adolescent patient with ulcerative colitis . Case Rep Ophthalmol Med 2011 ; 2011 : 963583 . Google Scholar PubMed 32. Falavarjani KG , Parvaresh MM , Shahraki K , Nekoozadeh S , Amirfarhangi A . Central retinal artery occlusion in Crohn disease . J Am Assoc Pediatr Ophthalmol Strabismus 2012 ; 16 : 392 – 3 . Google Scholar CrossRef Search ADS 33. Lapsia S , Meyer R , Abazari A , Usmani K , Gathungu G . Bilateral central retinal vein occlusion in a patient with ulcerative colitis and antiphospholipid antibody syndrome . J Pediatr Gastroenterol Nutr 2016 ; 62 : e25 – 6 . Google Scholar CrossRef Search ADS PubMed 34. Young RS , Hodes BL , Cruse RP , Koch KL , Garovoy MR . Orbital pseudotumor and Crohn disease . J Pediatr 1981 ; 99 : 250 – 2 . Google Scholar CrossRef Search ADS PubMed 35. Camfield PR , White M , Warner HA , Lythgoe C . Orbital pseudotumor and Crohn disease . J Pediatr 1982 ; 101 : 157 – 8 . Google Scholar CrossRef Search ADS PubMed 36. Weinstein JM , Koch K , Lane S . Orbital pseudotumor in Crohn’s colitis . Ann Ophthalmol 1984 ; 16 : 275 – 8 . Google Scholar PubMed 37. Squires RH Jr , Zwiener RJ , Kennedy RH . Orbital myositis and Crohn’s disease . J Pediatr Gastroenterol Nutr 1992 ; 15 : 448 – 51 . Google Scholar CrossRef Search ADS PubMed 38. Durno CA , Ehrlich R , Taylor R , Buncic JR , Hughes P , Griffiths AM . Keeping an eye on Crohn’s disease: orbital myositis as the presenting symptom . Can J Gastroenterol 1997 ; 11 : 497 – 500 . Google Scholar CrossRef Search ADS PubMed 39. Tan JHT , Arkachaisri T , Das L , Chu HP . Orbital pseudotumour as a presentation of paediatric ulcerative colitis . Singapore Med J 2014 ; 55 : 169 – 71 . Google Scholar CrossRef Search ADS 40. Vargason CW , Mawn LA . Orbital myositis as both a presenting and associated extraintestinal sign of Crohn’s disease . Ophthal Plast Reconstr Surg 2015 ; 33 ( Suppl 1): S158– 60 . Google Scholar CrossRef Search ADS 41. Thomas BJ , Emanuelli AA , Berrocal AM . Unilateral choroidal neovascular membrane as a herald lesion for Crohn’s disease . Ophthalmic Surg Lasers Imaging Retina 2014 ; 45 : 62 – 5 . Google Scholar CrossRef Search ADS PubMed 42. Greninger DA , Yoon MK , Bloomer MM , Keyser R , Kersten RC . Extraintestinal Crohn disease causing bilateral nasolacrimal duct obstruction . Ophthal Plast Reconstr Surg 2012 ; 28 : e55 – 6 . Google Scholar CrossRef Search ADS PubMed 43. Rafiei N , Tabandeh H , Hirschbein M . Bilateral dacroadenitis associated with acute Crohn’s disease . Eye [Lond] 2006 ; 20 : 1372 – 3 . Google Scholar PubMed 44. Mrugacz M , Sredzińska-Kita D , Cyrta-Jarocka E , Bakunowicz-Lazarczyk A . Dry eye syndrome and cataract as ocular manifestations of Crohn’s disease . Klin Oczna 2005 ; 107 : 509 – 10 . Google Scholar PubMed 45. Paroli MP , Spinucci G , Bruscolini A , La Cava M , Abicca I . Uveitis preceding Crohn’s disease by 8 years . Int Ophthalmol 2011 ; 31 : 413 – 5 . Google Scholar CrossRef Search ADS PubMed 46. Girardin M , Waschke KA , Seidman EG . A case of acute loss of vision as the presenting symptom of Crohn’s disease . Nat Clin Pract Gastroenterol Hepatol 2007 ; 4 : 695 – 8 . Google Scholar CrossRef Search ADS PubMed 47. Symeonidis C , Matsou A , Tzetzi D , Dermenoudi M , Brazitikos P , Mataftsi A . Amblyopia due to intermediate uveitis as the presenting symptom of Crohn’s disease in a 6-year-old boy . J AAPOS 2017 ; 21 : 512– 4 . Google Scholar CrossRef Search ADS PubMed 48. Read RW , Weiss AH , Sherry DD . Episcleritis in childhood . Ophthalmology 1999 ; 106 : 2377 – 9 . Google Scholar CrossRef Search ADS PubMed 49. Fasci-Spurio F , Thompson A , Madill S , Koay P , Mansfield D , Satsangi J . Sight-threatening keratopathy complicating anti-TNF therapy in Crohn’s disease: a case report . Inflamm Bowel Dis 2014 ; 20 : E2 – 3 . Google Scholar CrossRef Search ADS PubMed 50. Seo JK , Yeon KM , Chi JG . Inflammatory bowel disease in children - clinical, endoscopic, radiologic and histopathologic investigation . J Korean Med Sci 1992 ; 7 : 221 – 35 . Google Scholar CrossRef Search ADS PubMed 51. Blase WP , Knox DL , Green WR . Granulomatous conjunctivitis in a patient with Crohn’s disease . Br J Ophthalmol 1984 ; 68 : 901 – 3 . Google Scholar CrossRef Search ADS PubMed 52. Barabino AV , Gandullia P , Calvi A , Vignola S , Arrigo S , Marco RD . Sudden blindness in a child with Crohn’s disease . World J Gastroenterol 2011 ; 17 : 4344 – 6 . Google Scholar CrossRef Search ADS PubMed 53. Shoari M , Katz BJ . Recurrent neuroretinitis in an adolescent with ulcerative colitis . J Neuroophthalmol 2005 ; 25 : 286 – 8 . Google Scholar CrossRef Search ADS PubMed 54. Taylor SR , McCluskey P , Lightman S . The ocular manifestations of inflammatory bowel disease . Curr Opin Ophthalmol 2006 ; 17 : 538 – 44 . Google Scholar CrossRef Search ADS PubMed 55. Vavricka SR , Schoepfer A , Scharl M , Lakatos PL , Navarini A , Rogler G . Extraintestinal manifestations of inflammatory bowel disease . Inflamm Bowel Dis 2015 ; 21 : 1982 – 92 . Google Scholar CrossRef Search ADS PubMed 56. Zippi M , Corrado C , Pica R , et al. Extraintestinal manifestations in a large series of Italian inflammatory bowel disease patients . World J Gastroenterol 2014 ; 20 : 17463 – 7 . Google Scholar CrossRef Search ADS PubMed 57. Greenstein AJ , Janowitz HD , Sachar DB . The extraintestinal complications of Crohn’s disease and ulcerative colitis: a study of 700 patients . Medicine [Baltimore] 1976 ; 55 : 401 – 12 . Google Scholar CrossRef Search ADS PubMed 58. Eidelwein AP , Thompson R , Fiorino K , Abadom V , Oliva-Hemker M . Disease presentation and clinical course in black and white children with inflammatory bowel disease . J Pediatr Gastroenterol Nutr 2007 ; 44 : 555 – 60 . Google Scholar CrossRef Search ADS PubMed 59. White JM , O’Connor S , Winter HS , et al. Inflammatory bowel disease in African American children compared with other racial/ethnic groups in a multicenter registry . Clin Gastroenterol Hepatol 2008 ; 6 : 1361 – 9 . Google Scholar CrossRef Search ADS PubMed 60. Basu D , Lopez I , Kulkarni A , Sellin JH . Impact of race and ethnicity on inflammatory bowel disease . Am J Gastroenterol 2005 ; 100 : 2254 – 61 . Google Scholar CrossRef Search ADS PubMed 61. Nguyen GC , Torres EA , Regueiro M , et al. Inflammatory bowel disease characteristics among African Americans, Hispanics, and non-Hispanic Whites: characterization of a large North American cohort . Am J Gastroenterol 2006 ; 101 : 1012 – 23 . Google Scholar CrossRef Search ADS PubMed 62. Hou JK , El-Serag H , Thirumurthi S . Distribution and manifestations of inflammatory bowel disease in Asians, Hispanics, and African Americans: a systematic review . Am J Gastroenterol 2009 ; 104 : 2100 – 9 . Google Scholar CrossRef Search ADS PubMed 63. Löfberg R , Louis EV , Reinisch W , et al. Adalimumab produces clinical remission and reduces extraintestinal manifestations in Crohn’s disease: results from CARE . Inflamm Bowel Dis 2012 ; 18 : 1 – 9 . Google Scholar CrossRef Search ADS PubMed 64. Peyrin-Biroulet L , Van Assche G , Gómez-Ulloa D , et al. Systematic review of tumor necrosis factor antagonists in extraintestinal manifestations in inflammatory bowel disease . Clin Gastroenterol Hepatol 2017 ; 15 : 25 – 36.e27 . Google Scholar CrossRef Search ADS PubMed 65. Horai R , Zárate-Bladés CR , Dillenburg-Pilla P , et al. Microbiota-dependent activation of an autoreactive T cell receptor provokes autoimmunity in an immunologically privileged site . Immunity 2015 ; 43 : 343 – 53 . Google Scholar CrossRef Search ADS PubMed 66. Heiligenhaus A , Niewerth M , Ganser G , Heinz C , Minden K ; German Uveitis in Childhood Study Group . Prevalence and complications of uveitis in juvenile idiopathic arthritis in a population-based nation-wide study in Germany: suggested modification of the current screening guidelines . Rheumatology [Oxford] 2007 ; 46 : 1015 – 9 . Google Scholar CrossRef Search ADS PubMed 67. Malgarinos G , Giannakoulopoulou E , Mastrangelis A , et al. Cataract development as a complication of corticosteroid treatment in a young patient with ulcerative colitis . Ann Gastroenterol 2006 ; 19 : 358 – 9 . 68. Skalka HW , Prchal JT . Effect of corticosteroids on cataract formation . Arch Ophthalmol 1980 ; 98 : 1773 – 7 . Google Scholar CrossRef Search ADS PubMed 69. Katsanos A , Asproudis I , Katsanos KH , Dastiridou AI , Aspiotis M , Tsianos EV . Orbital and optic nerve complications of inflammatory bowel disease . J Crohns Colitis 2013 ; 7 : 683 – 93 . Google Scholar CrossRef Search ADS PubMed 70. Matsuo T , Yamaoka A . Retinal vasculitis revealed by fluorescein angiography in patients with inflammatory bowel disease . Jpn J Ophthalmol 1998 ; 42 : 398 – 400 . Google Scholar CrossRef Search ADS PubMed 71. Verbraak FD , Schreinemachers MC , Tiller A , van Deventer SJ , de Smet MD . Prevalence of subclinical anterior uveitis in adult patients with inflammatory bowel disease . Br J Ophthalmol 2001 ; 85 : 219 – 21 . Google Scholar CrossRef Search ADS PubMed 72. DeFilippis EM , Sockolow R , Barfield E . Health care maintenance for the pediatric patient with inflammatory bowel disease . Pediatrics 2016 ; 138 : e20151971 . Google Scholar CrossRef Search ADS PubMed Copyright © 2018 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Crohn's and Colitis Oxford University Press

Ocular Manifestations of Paediatric Inflammatory Bowel Disease: A Systematic Review and Meta-analysis

Journal of Crohn's and Colitis , Volume Advance Article (7) – Mar 6, 2018

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Elsevier Science
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Copyright © 2018 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com
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1873-9946
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1876-4479
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10.1093/ecco-jcc/jjy029
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Abstract

Abstract Background and Aims Ocular extraintestinal manifestations [O-EIMs] are known complications of Crohn’s disease [CD], ulcerative colitis [UC], and inflammatory bowel disease unclassified [IBD-U]. However, data on their prevalence in children are scarce and there are no clear recommendations on what follow-up should be offered. We aimed to review available data on O-EIMs in children. Methods In January 2018, we performed a systematic review of published English literature using PubMed and EMBASE databases and disease-specific queries. Results Fifteen studies [7467 patients] reported data on O-EIMs prevalence in children. Overall prevalence of O-EIMs was 0.62–1.82%. Uveitis was the most common O-EIM. Meta-analysis showed that children with CD are at increased risk of O-EIMs as compared with children with UC and IBD-U (odds ratio [OR] 2.70, 95% confidence interval [CI] 1.51–4.83). Five studies [357 patients] reported data on ophthalmological screening in asymptomatic children: mild asymptomatic uveitis was identified in a variable proportion of patients [1.06–23.1%], more frequently in male patients with CD and colonic involvement. No evidence of ocular complications from untreated uveitis was detected. A total of 23 case reports [24 patients] were identified. Conclusions Data on O-EIMs in children are scarce. Prevalence of O-EIMs is lower than in adults but may be underestimated because of the possibility of asymptomatic uveitis; however, the long-term significance of this condition is unknown. Children with CD may be at increased risk of O-EIMs. No recommendations on routine ophthalmological examination can be made, but a low threshold for ophthalmological referral should be maintained. Larger studies in paediatric IBD populations are needed. Ocular, extraintestinal manifestations, eye, IBD, children 1. Introduction Inflammatory bowel disease [IBD], including Crohn’s disease [CD], ulcerative colitis [UC], and IBD-unclassified [IBD-U], are chronic inflammatory disorders mainly affecting the gastrointestinal tract. They are associated with various extraintestinal manifestations [EIMs], which affect approximately 10% to 40% of patients1–3 and may potentially involve almost any organ, even before gastrointestinal symptoms appear. Ocular EIMs [O-EIMs] have been recognised since the early descriptions by Crohn,4 and are among the most common EIMs. Uveitis and episcleritis are among the most commonly reported conditions in adult patients, with a prevalence between 2% and 6% in large cohort studies.3,5,6 However, when a wider spectrum of ocular conditions is considered, a higher prevalence has been reported.6–9 O-EIMs may be associated with potentially severe outcomes. Uveitis, in particular, is associated with ocular pain, photophobia, and blurred vision, and when untreated may lead to several ocular complications, including keratopathy, cataract, glaucoma, posterior synechiae, cystoid macular oedema, and permanent vision loss. Other rarer, but potentially severe, ocular manifestations in patients with IBD include retinal vasculitis, central retinal artery/vein occlusion, retrobulbar neuritis, keratopathy, and orbital myositis. Data on O-EIMs prevalence and clinical course in children are scarce and there are no clear recommendations on which ophthalmological investigations and what follow-up should be offered—unlike other paediatric inflammatory disorders, such as juvenile idiopathic arthritis, for which an ophthalmological screening schedule has been developed.10 We aimed to review published data on the prevalence and clinical course of O-EIMs from observational studies in children with IBD, in order to better define their epidemiology and clinical characteristics, as well as possibly identifying clinical phenotypes that may be associated with a higher risk of ocular involvement. 2. Methods We performed a systematic review of O-EIMs in IBD children according to the MOOSE guidelines.11 We searched PubMed and EMBASE databases for studies published from inception to January 31, 2018, using the following queries: [1] [uveitis OR scleritis OR episcleritis OR iritis OR iridocyclitis OR ‘pars planitis’ OR choroiditis OR chorioretinitis OR retinitis OR papillitis OR ocular OR eye OR ophthalmologic OR ophthalmic OR orbital OR retinal OR optic OR dacryoadenitis OR keratopathy OR corneal OR conjunctivitis OR blepharitis OR cataract OR intra-ocular OR ‘visual acuity’ OR blindness OR uveal OR lacrimal] AND [Crohn OR ‘ulcerative colitis’ OR ‘inflammatory bowel disease’]; [2] [‘extraintestinal manifestation’ OR ‘extraintestinal manifestation’ OR ‘extraintestinal manifestations’ OR ‘extraintestinal manifestations’] AND [children OR pediatric] AND [‘Crohn’ or ‘ulcerative colitis’ OR ‘inflammatory bowel disease’]. 2.1. Data selection Two authors [GO, SN] independently reviewed search results and found a consensus on the articles to be included. Articles references were also considered for additional studies. To be analysed, studies had to report original data on O-EIMs in children with IBD. We included observational studies, as well as case reports. Limits related to age [0–18 years] and languages [English] were applied. Abstracts and unpublished studies were not included. If studies contained data from both adult and paediatric IBD patients, data from the two populations had to be clearly discernible. When articles contained potentially relevant data not fully reported, the authors were contacted by email for further information. Only in two cases were contacted authors able to provide the requested information, which were therefore included in our review, whereas the other authors declared their inability to provide complete data. 2.2. Meta-analysis Mantel-Haenszel weighting and random effects models were used. Statistical heterogeneity across studies was measured using the Cochran chi square test [p < 0.1 considered significant] and the I2 statistic. Variance was evaluated by means of tau.2 All statistical tests were two sided using an α level of 0.05. Publication bias was assessed by funnel plot. The meta-analyses were conducted with the statistical software Review Manager [RevMan] version 5.3 [The Cochrane Collaboration, 2014, Copenhagen, Denmark]. 3. Results We retrieved 1499 and 264 articles from the query one and two, respectively. We excluded 1470 and 247 articles because they did not meet inclusion criteria. Seven articles were found through both queries. Four other articles were found through the reference list of the included articles. Finally, we selected 43 articles for the analysis [Figure 1]. Figure 1. View largeDownload slide Flow chart of systematic literature search and selection process for systematic review. Figure 1. View largeDownload slide Flow chart of systematic literature search and selection process for systematic review. 3.1. Prevalence of O-EIMs in children Fifteen studies, including a total of 7467 patients, reported the prevalence of symptomatic ocular complications in children [Table 1].12–25 Substantial heterogeneity was present among studies. Timing of data collection varied, as some studies included only O-EIMs present at IBD diagnosis whereas others also considered O-EIMs appearing during follow-up. Studies also differed for O-EIMs inclusion criteria, since some authors reported data only for uveitis, whereas others also included other O-EIMs [e.g. episcleritis, papilledoema, corneal infiltrates], and other articles generically reported ‘ocular manifestations’ without further details. Finally, the methodology of O-EIMs ascertainment was poorly described or not reported in most studies, making comparative evaluation difficult to perform. Table 1. Studies reporting prevalence of O-EIMs in IBD children [ordered by population size]. No. of IBD patients O-EIMs considered Timing of data collection O-EIMs prevalence O-EIMs prevalence according to IBD type CD UC IBD-U Jose et al. 12 1649 Uveitis, papilleodema, Corneal infiltrates During follow-up [only first-appearing EIMs] 1.63% [27/1649] - - - Card et al.13 1594 Uveitis During follow-up 1.63% [26/1594] 2.07% [21/1014] 0.86% [5/580] - Castro et al.14 1576 Ocular manifestations, not better specified At diagnosis 1.07% [17/1576] 1.73% [11/635] 0.74% [6/810] 0% [0/131] Dotson et al.15 1009 Uveitis During follow-up 0.69% [7/1009] 0.82% [6/728] 0.36% [1/281] - Dimakou et al.16 483 Ocular manifestations, not better specified At diagnosis 0.62% [3/483] 0.60% [1/167] 0.37% [1/267] 2.04% [1/49] Greuter et al.17 329 Uveitis During follow-up 1.82% [6/329] 2.9% [5/173] 0.64% [1/156]a Duricova et al.18 158 Uveitis At diagnosis 1.27% [2/158] - 1.27% [2/158] - Cakir et al.19 127 Uveitis At diagnosis 1.57% [2/127] 3.4% [1/29] 1.1% [1/90] - Gower-Rousseau et al.20 113 Uveitis During follow-up 3.54% [4/113] - 3.54% [4/113] - Martinelli et al. 21 111 Uveitis During follow-up 1.80% [2/111] - 1.80% [2/111] - Saadah 22 96 Uveitis, keratitis At diagnosis 2.11% [2/96] 2.11% [2/96] - - Naviglio et al. 23 94 Uveitis During follow-up 1.06% [1/94] 2.17% [1/46] 0% [0/46] 0% [0/2] Lee et al. 24 73 Uveitis During follow-up 1.37% [1/73] 1.37% [1/73] - - Abdul Aziz 25 55 Uveitis At diagnosis 1.81% [1/55] 10% [1/10] 0% [0/34] 0% [0/11] No. of IBD patients O-EIMs considered Timing of data collection O-EIMs prevalence O-EIMs prevalence according to IBD type CD UC IBD-U Jose et al. 12 1649 Uveitis, papilleodema, Corneal infiltrates During follow-up [only first-appearing EIMs] 1.63% [27/1649] - - - Card et al.13 1594 Uveitis During follow-up 1.63% [26/1594] 2.07% [21/1014] 0.86% [5/580] - Castro et al.14 1576 Ocular manifestations, not better specified At diagnosis 1.07% [17/1576] 1.73% [11/635] 0.74% [6/810] 0% [0/131] Dotson et al.15 1009 Uveitis During follow-up 0.69% [7/1009] 0.82% [6/728] 0.36% [1/281] - Dimakou et al.16 483 Ocular manifestations, not better specified At diagnosis 0.62% [3/483] 0.60% [1/167] 0.37% [1/267] 2.04% [1/49] Greuter et al.17 329 Uveitis During follow-up 1.82% [6/329] 2.9% [5/173] 0.64% [1/156]a Duricova et al.18 158 Uveitis At diagnosis 1.27% [2/158] - 1.27% [2/158] - Cakir et al.19 127 Uveitis At diagnosis 1.57% [2/127] 3.4% [1/29] 1.1% [1/90] - Gower-Rousseau et al.20 113 Uveitis During follow-up 3.54% [4/113] - 3.54% [4/113] - Martinelli et al. 21 111 Uveitis During follow-up 1.80% [2/111] - 1.80% [2/111] - Saadah 22 96 Uveitis, keratitis At diagnosis 2.11% [2/96] 2.11% [2/96] - - Naviglio et al. 23 94 Uveitis During follow-up 1.06% [1/94] 2.17% [1/46] 0% [0/46] 0% [0/2] Lee et al. 24 73 Uveitis During follow-up 1.37% [1/73] 1.37% [1/73] - - Abdul Aziz 25 55 Uveitis At diagnosis 1.81% [1/55] 10% [1/10] 0% [0/34] 0% [0/11] IBD-U, inflammatory bowel disease unclassified; O-EIM, ocular extraintestinal manifestation; CD, Crohn’s disease; UC, ulcerative colitis. aAggregate data [UC+IBD-U]. View Large Table 1. Studies reporting prevalence of O-EIMs in IBD children [ordered by population size]. No. of IBD patients O-EIMs considered Timing of data collection O-EIMs prevalence O-EIMs prevalence according to IBD type CD UC IBD-U Jose et al. 12 1649 Uveitis, papilleodema, Corneal infiltrates During follow-up [only first-appearing EIMs] 1.63% [27/1649] - - - Card et al.13 1594 Uveitis During follow-up 1.63% [26/1594] 2.07% [21/1014] 0.86% [5/580] - Castro et al.14 1576 Ocular manifestations, not better specified At diagnosis 1.07% [17/1576] 1.73% [11/635] 0.74% [6/810] 0% [0/131] Dotson et al.15 1009 Uveitis During follow-up 0.69% [7/1009] 0.82% [6/728] 0.36% [1/281] - Dimakou et al.16 483 Ocular manifestations, not better specified At diagnosis 0.62% [3/483] 0.60% [1/167] 0.37% [1/267] 2.04% [1/49] Greuter et al.17 329 Uveitis During follow-up 1.82% [6/329] 2.9% [5/173] 0.64% [1/156]a Duricova et al.18 158 Uveitis At diagnosis 1.27% [2/158] - 1.27% [2/158] - Cakir et al.19 127 Uveitis At diagnosis 1.57% [2/127] 3.4% [1/29] 1.1% [1/90] - Gower-Rousseau et al.20 113 Uveitis During follow-up 3.54% [4/113] - 3.54% [4/113] - Martinelli et al. 21 111 Uveitis During follow-up 1.80% [2/111] - 1.80% [2/111] - Saadah 22 96 Uveitis, keratitis At diagnosis 2.11% [2/96] 2.11% [2/96] - - Naviglio et al. 23 94 Uveitis During follow-up 1.06% [1/94] 2.17% [1/46] 0% [0/46] 0% [0/2] Lee et al. 24 73 Uveitis During follow-up 1.37% [1/73] 1.37% [1/73] - - Abdul Aziz 25 55 Uveitis At diagnosis 1.81% [1/55] 10% [1/10] 0% [0/34] 0% [0/11] No. of IBD patients O-EIMs considered Timing of data collection O-EIMs prevalence O-EIMs prevalence according to IBD type CD UC IBD-U Jose et al. 12 1649 Uveitis, papilleodema, Corneal infiltrates During follow-up [only first-appearing EIMs] 1.63% [27/1649] - - - Card et al.13 1594 Uveitis During follow-up 1.63% [26/1594] 2.07% [21/1014] 0.86% [5/580] - Castro et al.14 1576 Ocular manifestations, not better specified At diagnosis 1.07% [17/1576] 1.73% [11/635] 0.74% [6/810] 0% [0/131] Dotson et al.15 1009 Uveitis During follow-up 0.69% [7/1009] 0.82% [6/728] 0.36% [1/281] - Dimakou et al.16 483 Ocular manifestations, not better specified At diagnosis 0.62% [3/483] 0.60% [1/167] 0.37% [1/267] 2.04% [1/49] Greuter et al.17 329 Uveitis During follow-up 1.82% [6/329] 2.9% [5/173] 0.64% [1/156]a Duricova et al.18 158 Uveitis At diagnosis 1.27% [2/158] - 1.27% [2/158] - Cakir et al.19 127 Uveitis At diagnosis 1.57% [2/127] 3.4% [1/29] 1.1% [1/90] - Gower-Rousseau et al.20 113 Uveitis During follow-up 3.54% [4/113] - 3.54% [4/113] - Martinelli et al. 21 111 Uveitis During follow-up 1.80% [2/111] - 1.80% [2/111] - Saadah 22 96 Uveitis, keratitis At diagnosis 2.11% [2/96] 2.11% [2/96] - - Naviglio et al. 23 94 Uveitis During follow-up 1.06% [1/94] 2.17% [1/46] 0% [0/46] 0% [0/2] Lee et al. 24 73 Uveitis During follow-up 1.37% [1/73] 1.37% [1/73] - - Abdul Aziz 25 55 Uveitis At diagnosis 1.81% [1/55] 10% [1/10] 0% [0/34] 0% [0/11] IBD-U, inflammatory bowel disease unclassified; O-EIM, ocular extraintestinal manifestation; CD, Crohn’s disease; UC, ulcerative colitis. aAggregate data [UC+IBD-U]. View Large Overall prevalence of O-EIMs in IBD at diagnosis ranged from 0.62% [3/483 patients, Dimakou et al.16] to 1.81% [1/55 patients, Abdul Aziz et al.25]. Prevalence during follow-up ranged from 0.69% [7/1009 patients, Dotson et al.15] to 1.82% [6/329 patients, Greuter et al.17]. The largest available study [Jose et al.12] reported data about the first EIM in a cohort of 1649 North-American children with IBD. Among 387 children with a first EIM, 7% [27/387] had an O-EIM; 52 and 13 out of 387 children developed also a second and a third one, respectively, yet data on these EIMs were not detailed and, when contacted authors, could not provide further information; however, an overall incidence rate for anterior uveitis of 0.18 per 100 patient-years was reported. This study was also the only one among larger studies to analyse the prevalence of different types of O-EIMs, with uveitis being the most commonly reported condition [17 patients out of 27 with O-EIMs], followed by papilledoema and corneal infiltrates [7 patients—aggregate data]. A trend towards greater prevalence of O-EIMs in children with CD emerged from several studies, yet this difference did not reach statistical significance, possibly because of the limited number of patients included in each study. We performed a meta-analysis to assess the risk of O-EIMs in children according to the different IBD diagnoses. We compared the prevalence of O-EIMs in children with CD vs children with UC and IBD-U; these two latter groups of patients were analysed together because not all the studies differentiated between them. Only studies including both categories of patients were included in the meta-analysis, to allow direct between-groups comparison. Children with CD were found to be at increased risk of O-EIMs [odds ratio 2.70, 95% CI 1.51–4.83, p = 0.0008] [Figure 2]. No significant heterogeneity was detected among studies as evaluated by Cochran’s chi square test [p = 0.96] and I2 statistic [I2 = 0%]; nevertheless, data on O-EIMs diagnosis criteria and on patients’ characteristics for each study were scarce or absent. Publication bias did not seem to be relevant as evaluated by funnel plot [data not shown], yet the number of available studies was low. Figure 2. View largeDownload slide Forest plot for prevalence of ocular extraintestinal manifestations [O-EIMs] among children with inflammatory bowel disease [IBD]. Figure 2. View largeDownload slide Forest plot for prevalence of ocular extraintestinal manifestations [O-EIMs] among children with inflammatory bowel disease [IBD]. Dotson et al.15 evaluated the association of O-EIMs with intestinal disease localisation, presence of perianal disease, and patient’s age and sex, but no significant association was found. One study [Gower-Rousseau et al.20] reported a remarkably high prevalence of uveitis during follow-up in children with UC [four of 113 patients, 3.54%]. However, this study was relatively small and was performed only in patients with UC. Greuter et al.17 also included data on timing of uveitis appearance in their population: six of 329 patients in their cohort had a diagnosis of uveitis, which occurred at a median time of approximately 7 years after IBD diagnosis, with one case preceding intestinal disease onset.17 The same study group published also a separate sub-analysis of patients from the same database [the Swiss IBD Cohort Study] evaluated at 10 years [range 108–132 months] of follow-up.26 After 10 years, age at IBD diagnosis did not appear to influence risk of uveitis, with similar incidence rates in patients with IBD diagnosis <10 years of age, <17 years of age, <40 years of age, and >40 years of age. No study did provide information about the prevalence of O-EIMs according to the patients’ ethnicity. Jose et al. included data on patients’ ethnicity, reporting no difference on the overall risk of EIMs, but no information was available for O-EIMs.12 Finally, few studies provided details about concurrent treatments: Dotson et al.15 observed a protective effect of treatment with mesalamine/sulphasalazine, infliximab, and immunomodulators on the overall risk EIMs for patients with moderate to severe disease as compared with patients who had not received these treatments; no data, however, were specifically available for O-EIMs.15 Finally, Greuter et al.17 reported the effect of treatment with anti-tumour necrosis factor [TNF] on uveitis: two patients out of three experienced uveitis improvement with treatment; however, in two patients uveitis appeared during anti-TNF treatment. 3.2. Screening for O-EIMs in children Five studies [including 357 patients] reported data on small cohorts of asymptomatic children who underwent ophthalmological screening regardless of the presence of ocular symptoms.23,27–30 Four studies [including 299 patients] included full ophthalmological evaluation [Table 2], and a fifth study [Tripathi et al.30] evaluated only ocular side effects of corticosteroid treatment. Table 2. Studies reporting full ophthalmological screening in children with IBD. No. patients Asymptomatic uveitis Cataract Overall CD UC Daum et al.27 26 23.08% [6/26] 31.58% [6/19] 0% [0/7] 0% Hofley et al.28 147 4.08% [6/147] 6.19% [6/97] 0% [0/50] 0% Rychwalski et al.29 32 12.50% [4/32] 16.67% [3/18] 7.14% [1/14] 15.63% [5/32] Naviglio et al.23 94 1.06% [1/94] 2.17% [1/46] 0% [0/46] 1.06% [1/94] Total 299 4.86% [18/299] 9.44% [17/180] 0.85% [1/117] 2.00% [6/299] No. patients Asymptomatic uveitis Cataract Overall CD UC Daum et al.27 26 23.08% [6/26] 31.58% [6/19] 0% [0/7] 0% Hofley et al.28 147 4.08% [6/147] 6.19% [6/97] 0% [0/50] 0% Rychwalski et al.29 32 12.50% [4/32] 16.67% [3/18] 7.14% [1/14] 15.63% [5/32] Naviglio et al.23 94 1.06% [1/94] 2.17% [1/46] 0% [0/46] 1.06% [1/94] Total 299 4.86% [18/299] 9.44% [17/180] 0.85% [1/117] 2.00% [6/299] IBD-U, inflammatory bowel disease unclassified; O-EIM, ocular extraintestinal manifestation; CD, Crohn’s disease; UC, ulcerative colitis View Large Table 2. Studies reporting full ophthalmological screening in children with IBD. No. patients Asymptomatic uveitis Cataract Overall CD UC Daum et al.27 26 23.08% [6/26] 31.58% [6/19] 0% [0/7] 0% Hofley et al.28 147 4.08% [6/147] 6.19% [6/97] 0% [0/50] 0% Rychwalski et al.29 32 12.50% [4/32] 16.67% [3/18] 7.14% [1/14] 15.63% [5/32] Naviglio et al.23 94 1.06% [1/94] 2.17% [1/46] 0% [0/46] 1.06% [1/94] Total 299 4.86% [18/299] 9.44% [17/180] 0.85% [1/117] 2.00% [6/299] No. patients Asymptomatic uveitis Cataract Overall CD UC Daum et al.27 26 23.08% [6/26] 31.58% [6/19] 0% [0/7] 0% Hofley et al.28 147 4.08% [6/147] 6.19% [6/97] 0% [0/50] 0% Rychwalski et al.29 32 12.50% [4/32] 16.67% [3/18] 7.14% [1/14] 15.63% [5/32] Naviglio et al.23 94 1.06% [1/94] 2.17% [1/46] 0% [0/46] 1.06% [1/94] Total 299 4.86% [18/299] 9.44% [17/180] 0.85% [1/117] 2.00% [6/299] IBD-U, inflammatory bowel disease unclassified; O-EIM, ocular extraintestinal manifestation; CD, Crohn’s disease; UC, ulcerative colitis View Large Studies reporting full ophthalmological evaluation found asymptomatic uveitis [i.e. subclinical uveitis detected only by slit lamp examination] in several children with IBD. Three studies [Daum et al., 197927; Hofley et al., 199328; Rychwalski et al., 199729] reported a prevalence of asymptomatic uveitis substantially higher than prevalence of O-EIMs from cohort studies: 4.1% [6/147 patients, Hofley et al.], 12.5% [4/32 patients, Rychwalski et al.], and 23.1% [6/26 patients, Daum et al.]. More recently, Naviglio et al.23 reported a lower prevalence [1/94 patients, 1.06%] of uveitis in a sample of paediatric patients with IBD who had undergone ophthalmological screening evaluation. In this study, only one patient was found to have asymptomatic anterior uveitis on screening slit lamp examination; the same patient also had a history of previous bilateral symptomatic [i.e. eye redness and discomfort] anterior uveitis 7 years earlier, at IBD onset. Uveitis had been treated with dexamethasone eye drops and had not recurred for the 7 years. No other patient had a history of O-EIMs diagnoses. Furthermore, no patient had ocular signs of complications from previous, unrecognised uveitis at ophthalmological evaluation. Considering combined data from these four studies, a total of 299 patients were screened [180 CD, 117 UC, and 2 IBD-U]. Asymptomatic uveitis was detected in 18/299 patients [4.86%] and was characterised as mild anterior uveitis in all patients. Asymptomatic uveitis was detected more frequently in CD [CD/UC = 17/1; prevalence in CD patients = 9.4%; prevalence in UC patients = 0.85%], adolescent [mean age 14.5 years], and male [M/F = 14/4] patients. Colonic involvement was prevalent [13 out of 14 patients for whom data are available]. Presence of HLA-B27 was reported only by Daum et al. [1/6 patients].27 Intestinal disease activity was not related to ocular inflammation [active intestinal disease in 6/12 patients with uveitis; no data available from Daum et al.]. In all cases of asymptomatic uveitis, no specific treatment was deemed necessary. Data on short-term follow-up [4–12 months] are available only for patients reported by Daum et al.27 and Naviglio et al.23: uveitis resolved in 6/7 patients overall [one patient was lost to follow-up]; the long-term outcomes were not reported. Posterior subcapsular cataract, a known adverse effect of corticosteroid treatment, was detected in six patients [five by Rychwalski et al.,29 one by Naviglio et al.,23 and in no patients from the other two studies] [overall prevalence 6/299 patients, 2.0%]. A fifth study, by Tripathi et al.,30 performed an ophthalmological evaluation targeted at ocular side effects of corticosteroid treatment.30 In all, 58 paediatric patients with IBD treated with corticosteroids, as well as 58 age-matched controls, were evaluated. Most patients [38/58] had received corticosteroid treatment for more than a year [range 1–104 months]. Posterior subcapsular cataract was detected in 12 patients [20.7%] and in none of the controls. Patients also had a significintra-ocantly higher intra-ocular pressure [15.89 +/- 4.11 mmHg vs 13.63 +/- 2.35 mmHg, p < 0.001], with 21 patients [36.2%] defined as ‘intra-ocular pressure responders’ [intra-ocular pressure ≥20 mmHg, or change ≥6 mmHg between visits, or a difference ≥6 mmHg between the two eyes]. Overall 30 patients [52%] had either cataract or abnormal intra-ocular pressure. Cataract risk was not correlated with the total dose of corticosteroids, duration of treatment, average daily dose, or number of days on higher doses, whereas increased intra-ocular pressure was correlated with average daily dose in the past 30 days. At follow-up visits, performed at 3–18 months after initial evaluation, dose-related changes in ophthalmological findings were observed. Notably, cataract regression was observed in two patients lowering the prednisone daily dose to less than 10 mg/day of prednisone. Similarly, increased ocular pressure responded to lowering of dose to less than 10 mg/day; on the other hand, an increase in corticosteroid dose was associated with abnormal intra-ocular pressure in some patients with previously normal findings. 3.3. Case reports We retrieved 23 case reports/case series including 24 children with O-EIMs [Table 3]. Reported conditions included: central retinal vein/artery occlusion,31–33 orbital myositis/orbital pseudotumour,34–40 choroidal neovascular membrane,41 nasolacrimal duct obstruction,42 dacryoadenitis,43 dry eyes syndrome,44 cataract,44 unilateral/bilateral uveitis,45–47 episcleritis,48 keratopathy/keratitis,49,50 granulomatous conjunctivitis,51 optic neuritis,52 and recurrent neuroretinitis.53 All patients presented with ocular symptoms when evaluated, including reduced visual acuity [even sudden vision loss], ocular pain/discomfort, redness, eyelid swelling, proptosis, photophobia, and diplopia. Considering all patients for whom detailed information were available, more patients were male [M/F = 14/8] and had CD [CD/UC = 18/5]. Mean age at O-EIM onset was 13 years [range 2–20 years]. Five patients were diagnosed with ophthalmological conditions before IBD onset, and in 11 patients they were present at IBD diagnosis. When O-EIMs occurred after IBD onset, latency ranged from 2 to 8 years. Complete resolution was reported in most cases of inflammatory complications [i.e. uveitis, orbital myositis/pseudotumour, neuroretinitis, and optic neuritis], but persistent visual impairment was reported in a 6-year-old boy with intermediate uveitis who had residual amblyopia despite resolution of uveitis.47 Treatment included systemic steroids in almost all reported cases; methotrexate was used in one case of orbital pseudotumour, leading to resolution.40 Vascular conditions [central retinal artery or vein occlusion, choroidal neovascular membrane] had a worse prognosis, with residual visual impairment in three out of four patients. Table 3. Case reports on ocular complications in children with IBD. 1st author, year Ocular signs and symptoms O-EIM diagnosis IBD O-EIM onset [y] IBD onset [y] Sex IBD localisation Other EIMs Therapy Outcome Symeonidis47 Low visual acuity Unilateral intermediate uveitis CD 6 6 [after 5 months] M Terminal ileum Arthritis Systemic steroids Resolved uveitis, persistent amblyopia Lapsia33 Low visual acuity Bilateral central retinal vein occlusion UC 19 17 M ND ND Enoxaparin, Bevacizumab, colectomy Improved visual acuity Vargason40 Eyelid swelling Orbital myositis CD 15 15 M Terminal ileum ND Systemic steroids methotrexate Resolved Tan39 Ocular pain and swelling Bilateral orbital pseudotumour UC 2 2 F Pancolitis Arthritis Vasculitis NSAIDs Resolved Thomas41 Low visual acuity Unilateral choroidal neovascular membrane CD 13 15 M ND ND Intravitreal bevacizumab Stabilised Fasci-Spurio49 Low visual acuity Bilateral rosacea-like keratopathy CD 16 16 M Pancolitis EN Acne rosacea Anti-TNF discontinuation Resolved Falavarjani32 Low visual acuity Unilateral central retinal artery occlusion CD 9 5 M ND ND None Optic nerve atrophy Greninger42 Epiphora, enlarged lacrimal sacs Bilateral granulomatous dacryocystitis CD 16 13 M Ileocolonic Granulomatous cheilitis External dacryocysto-rhinostomy ND Barabino52 Bilateral visual loss Optic neuritis CD 11 11 M Stomach, duodenum, colon ND Systemic steroids Resolved Paroli45 Bilateral ocular pain redness Bilateral anterior uveitis, optic disc oedema CD 4 12 M ND EN, arthritis aphthous stomatitis Topical and systemic steroids Resolved Vayalambrone31 Low visual acuity Nonischaemic central retinal vein occlusion UC 16 16 F ND ND ND Improved visual acuity Girardin46 Low visual acuity Photophobia Bilateral anterior uveitis CD 17 17 M Stomach, duodenum, ileocolonic ND Topical steroids Resolved Rafiei43 Bilateral upper eyelid swelling Bilateral dacryoadenitis CD 10 10 F Ileum, colon Arthralgia, aphthous stomatitis Systemic steroids Resolved Mrugacz44 Low visual acuity, ocular pain, redness, photophobia, foreign body sensation Dry eyes, bilateral posterior subcapsular cataract CD 11 4 F ND ND Hyaluronan eye drops [tears substitute] Dry eye syndrome resolved; stable cataract Shoari53 Low visual acuity, ocular pain Recurrent neuroretinitis UC 14 17 M Pancolitis ND Systemic steroids Improved visual acuity Read48 ND Episcleritis ND 16 ND M ND ND ND ND Durno38 Proptosis, periorbital swelling Orbital myositis CD 12 13 F Stomach, duodenum ileocolonic ND 5-ASA Resolved Squires37 Orbital pain diplopia Unilateral orbital myositis CD 20 12 M Ileocolonic ND Systemic steroids Resolved Seo50 ND Keratitis CD ND ND ND ND ND ND ND ND Chronic conjunctivitis UC ND ND ND ND ND ND ND Blase51 Bilateral eye redness Granulomatous conjunctivitis CD 13 13 M Rectum ND Systemic steroids Resolved Weinstein36 Ocular pain, diplopia, ptosis Unilateral orbital pseudotumour CD 17 17 F Colon ND Systemic steroids Resolved Camfield35 Ocular pain, photophobia Bilateral orbital pseudotumour CD 15 15 F Terminal ileum ND Systemic steroids Resolved Young34 Ocular pain, proptosis, diplopia Bilateral orbital pseudotumour CD 14 14 F Terminal ileum ND Systemic steroids, bowel resection Resolved 1st author, year Ocular signs and symptoms O-EIM diagnosis IBD O-EIM onset [y] IBD onset [y] Sex IBD localisation Other EIMs Therapy Outcome Symeonidis47 Low visual acuity Unilateral intermediate uveitis CD 6 6 [after 5 months] M Terminal ileum Arthritis Systemic steroids Resolved uveitis, persistent amblyopia Lapsia33 Low visual acuity Bilateral central retinal vein occlusion UC 19 17 M ND ND Enoxaparin, Bevacizumab, colectomy Improved visual acuity Vargason40 Eyelid swelling Orbital myositis CD 15 15 M Terminal ileum ND Systemic steroids methotrexate Resolved Tan39 Ocular pain and swelling Bilateral orbital pseudotumour UC 2 2 F Pancolitis Arthritis Vasculitis NSAIDs Resolved Thomas41 Low visual acuity Unilateral choroidal neovascular membrane CD 13 15 M ND ND Intravitreal bevacizumab Stabilised Fasci-Spurio49 Low visual acuity Bilateral rosacea-like keratopathy CD 16 16 M Pancolitis EN Acne rosacea Anti-TNF discontinuation Resolved Falavarjani32 Low visual acuity Unilateral central retinal artery occlusion CD 9 5 M ND ND None Optic nerve atrophy Greninger42 Epiphora, enlarged lacrimal sacs Bilateral granulomatous dacryocystitis CD 16 13 M Ileocolonic Granulomatous cheilitis External dacryocysto-rhinostomy ND Barabino52 Bilateral visual loss Optic neuritis CD 11 11 M Stomach, duodenum, colon ND Systemic steroids Resolved Paroli45 Bilateral ocular pain redness Bilateral anterior uveitis, optic disc oedema CD 4 12 M ND EN, arthritis aphthous stomatitis Topical and systemic steroids Resolved Vayalambrone31 Low visual acuity Nonischaemic central retinal vein occlusion UC 16 16 F ND ND ND Improved visual acuity Girardin46 Low visual acuity Photophobia Bilateral anterior uveitis CD 17 17 M Stomach, duodenum, ileocolonic ND Topical steroids Resolved Rafiei43 Bilateral upper eyelid swelling Bilateral dacryoadenitis CD 10 10 F Ileum, colon Arthralgia, aphthous stomatitis Systemic steroids Resolved Mrugacz44 Low visual acuity, ocular pain, redness, photophobia, foreign body sensation Dry eyes, bilateral posterior subcapsular cataract CD 11 4 F ND ND Hyaluronan eye drops [tears substitute] Dry eye syndrome resolved; stable cataract Shoari53 Low visual acuity, ocular pain Recurrent neuroretinitis UC 14 17 M Pancolitis ND Systemic steroids Improved visual acuity Read48 ND Episcleritis ND 16 ND M ND ND ND ND Durno38 Proptosis, periorbital swelling Orbital myositis CD 12 13 F Stomach, duodenum ileocolonic ND 5-ASA Resolved Squires37 Orbital pain diplopia Unilateral orbital myositis CD 20 12 M Ileocolonic ND Systemic steroids Resolved Seo50 ND Keratitis CD ND ND ND ND ND ND ND ND Chronic conjunctivitis UC ND ND ND ND ND ND ND Blase51 Bilateral eye redness Granulomatous conjunctivitis CD 13 13 M Rectum ND Systemic steroids Resolved Weinstein36 Ocular pain, diplopia, ptosis Unilateral orbital pseudotumour CD 17 17 F Colon ND Systemic steroids Resolved Camfield35 Ocular pain, photophobia Bilateral orbital pseudotumour CD 15 15 F Terminal ileum ND Systemic steroids Resolved Young34 Ocular pain, proptosis, diplopia Bilateral orbital pseudotumour CD 14 14 F Terminal ileum ND Systemic steroids, bowel resection Resolved IBD-U, inflammatory bowel disease unclassified; O-EIM, ocular extraintestinal manifestation; CD, Crohn’s disease; UC, ulcerative colitis; y, years; M, male; F female; ND, no data; NSAID, non-steroidal anti-inflammatory drug, EN, erythema nodosum, 5-ASA, mesalamine. View Large Table 3. Case reports on ocular complications in children with IBD. 1st author, year Ocular signs and symptoms O-EIM diagnosis IBD O-EIM onset [y] IBD onset [y] Sex IBD localisation Other EIMs Therapy Outcome Symeonidis47 Low visual acuity Unilateral intermediate uveitis CD 6 6 [after 5 months] M Terminal ileum Arthritis Systemic steroids Resolved uveitis, persistent amblyopia Lapsia33 Low visual acuity Bilateral central retinal vein occlusion UC 19 17 M ND ND Enoxaparin, Bevacizumab, colectomy Improved visual acuity Vargason40 Eyelid swelling Orbital myositis CD 15 15 M Terminal ileum ND Systemic steroids methotrexate Resolved Tan39 Ocular pain and swelling Bilateral orbital pseudotumour UC 2 2 F Pancolitis Arthritis Vasculitis NSAIDs Resolved Thomas41 Low visual acuity Unilateral choroidal neovascular membrane CD 13 15 M ND ND Intravitreal bevacizumab Stabilised Fasci-Spurio49 Low visual acuity Bilateral rosacea-like keratopathy CD 16 16 M Pancolitis EN Acne rosacea Anti-TNF discontinuation Resolved Falavarjani32 Low visual acuity Unilateral central retinal artery occlusion CD 9 5 M ND ND None Optic nerve atrophy Greninger42 Epiphora, enlarged lacrimal sacs Bilateral granulomatous dacryocystitis CD 16 13 M Ileocolonic Granulomatous cheilitis External dacryocysto-rhinostomy ND Barabino52 Bilateral visual loss Optic neuritis CD 11 11 M Stomach, duodenum, colon ND Systemic steroids Resolved Paroli45 Bilateral ocular pain redness Bilateral anterior uveitis, optic disc oedema CD 4 12 M ND EN, arthritis aphthous stomatitis Topical and systemic steroids Resolved Vayalambrone31 Low visual acuity Nonischaemic central retinal vein occlusion UC 16 16 F ND ND ND Improved visual acuity Girardin46 Low visual acuity Photophobia Bilateral anterior uveitis CD 17 17 M Stomach, duodenum, ileocolonic ND Topical steroids Resolved Rafiei43 Bilateral upper eyelid swelling Bilateral dacryoadenitis CD 10 10 F Ileum, colon Arthralgia, aphthous stomatitis Systemic steroids Resolved Mrugacz44 Low visual acuity, ocular pain, redness, photophobia, foreign body sensation Dry eyes, bilateral posterior subcapsular cataract CD 11 4 F ND ND Hyaluronan eye drops [tears substitute] Dry eye syndrome resolved; stable cataract Shoari53 Low visual acuity, ocular pain Recurrent neuroretinitis UC 14 17 M Pancolitis ND Systemic steroids Improved visual acuity Read48 ND Episcleritis ND 16 ND M ND ND ND ND Durno38 Proptosis, periorbital swelling Orbital myositis CD 12 13 F Stomach, duodenum ileocolonic ND 5-ASA Resolved Squires37 Orbital pain diplopia Unilateral orbital myositis CD 20 12 M Ileocolonic ND Systemic steroids Resolved Seo50 ND Keratitis CD ND ND ND ND ND ND ND ND Chronic conjunctivitis UC ND ND ND ND ND ND ND Blase51 Bilateral eye redness Granulomatous conjunctivitis CD 13 13 M Rectum ND Systemic steroids Resolved Weinstein36 Ocular pain, diplopia, ptosis Unilateral orbital pseudotumour CD 17 17 F Colon ND Systemic steroids Resolved Camfield35 Ocular pain, photophobia Bilateral orbital pseudotumour CD 15 15 F Terminal ileum ND Systemic steroids Resolved Young34 Ocular pain, proptosis, diplopia Bilateral orbital pseudotumour CD 14 14 F Terminal ileum ND Systemic steroids, bowel resection Resolved 1st author, year Ocular signs and symptoms O-EIM diagnosis IBD O-EIM onset [y] IBD onset [y] Sex IBD localisation Other EIMs Therapy Outcome Symeonidis47 Low visual acuity Unilateral intermediate uveitis CD 6 6 [after 5 months] M Terminal ileum Arthritis Systemic steroids Resolved uveitis, persistent amblyopia Lapsia33 Low visual acuity Bilateral central retinal vein occlusion UC 19 17 M ND ND Enoxaparin, Bevacizumab, colectomy Improved visual acuity Vargason40 Eyelid swelling Orbital myositis CD 15 15 M Terminal ileum ND Systemic steroids methotrexate Resolved Tan39 Ocular pain and swelling Bilateral orbital pseudotumour UC 2 2 F Pancolitis Arthritis Vasculitis NSAIDs Resolved Thomas41 Low visual acuity Unilateral choroidal neovascular membrane CD 13 15 M ND ND Intravitreal bevacizumab Stabilised Fasci-Spurio49 Low visual acuity Bilateral rosacea-like keratopathy CD 16 16 M Pancolitis EN Acne rosacea Anti-TNF discontinuation Resolved Falavarjani32 Low visual acuity Unilateral central retinal artery occlusion CD 9 5 M ND ND None Optic nerve atrophy Greninger42 Epiphora, enlarged lacrimal sacs Bilateral granulomatous dacryocystitis CD 16 13 M Ileocolonic Granulomatous cheilitis External dacryocysto-rhinostomy ND Barabino52 Bilateral visual loss Optic neuritis CD 11 11 M Stomach, duodenum, colon ND Systemic steroids Resolved Paroli45 Bilateral ocular pain redness Bilateral anterior uveitis, optic disc oedema CD 4 12 M ND EN, arthritis aphthous stomatitis Topical and systemic steroids Resolved Vayalambrone31 Low visual acuity Nonischaemic central retinal vein occlusion UC 16 16 F ND ND ND Improved visual acuity Girardin46 Low visual acuity Photophobia Bilateral anterior uveitis CD 17 17 M Stomach, duodenum, ileocolonic ND Topical steroids Resolved Rafiei43 Bilateral upper eyelid swelling Bilateral dacryoadenitis CD 10 10 F Ileum, colon Arthralgia, aphthous stomatitis Systemic steroids Resolved Mrugacz44 Low visual acuity, ocular pain, redness, photophobia, foreign body sensation Dry eyes, bilateral posterior subcapsular cataract CD 11 4 F ND ND Hyaluronan eye drops [tears substitute] Dry eye syndrome resolved; stable cataract Shoari53 Low visual acuity, ocular pain Recurrent neuroretinitis UC 14 17 M Pancolitis ND Systemic steroids Improved visual acuity Read48 ND Episcleritis ND 16 ND M ND ND ND ND Durno38 Proptosis, periorbital swelling Orbital myositis CD 12 13 F Stomach, duodenum ileocolonic ND 5-ASA Resolved Squires37 Orbital pain diplopia Unilateral orbital myositis CD 20 12 M Ileocolonic ND Systemic steroids Resolved Seo50 ND Keratitis CD ND ND ND ND ND ND ND ND Chronic conjunctivitis UC ND ND ND ND ND ND ND Blase51 Bilateral eye redness Granulomatous conjunctivitis CD 13 13 M Rectum ND Systemic steroids Resolved Weinstein36 Ocular pain, diplopia, ptosis Unilateral orbital pseudotumour CD 17 17 F Colon ND Systemic steroids Resolved Camfield35 Ocular pain, photophobia Bilateral orbital pseudotumour CD 15 15 F Terminal ileum ND Systemic steroids Resolved Young34 Ocular pain, proptosis, diplopia Bilateral orbital pseudotumour CD 14 14 F Terminal ileum ND Systemic steroids, bowel resection Resolved IBD-U, inflammatory bowel disease unclassified; O-EIM, ocular extraintestinal manifestation; CD, Crohn’s disease; UC, ulcerative colitis; y, years; M, male; F female; ND, no data; NSAID, non-steroidal anti-inflammatory drug, EN, erythema nodosum, 5-ASA, mesalamine. View Large 4. Discussion Data on ocular involvement in children with IBD are scarce and fragmented. Substantial heterogeneity among studies and several methodological issues currently limit the complete evaluation of this topic. Among cohort studies reporting prevalence of O-EIMs in children with IBD, inclusion criteria for O-EIMs were, in fact, highly variable, with some authors focusing only on selected conditions [e.g. uveitis] and others reporting the presence of ‘ocular manifestations’ without further specification. Furthermore, criteria for the diagnosis of O-EIMs are not fully defined in most studies. Notwithstanding these limitations, data from cohort studies indicate a lower prevalence of ocular involvement in children [0.6–1.8%] than in adults [2–6%]. Data on different types of O-EIMs are even scarcer, with only one report [Jose et al.12] showing different prevalence for selected ocular conditions [uveitis, papilledoema, corneal infiltrates]. According to this study, uveitis represents the most common O-EIM in children with IBD. Subtype and localisation of uveitis were not indicated, yet in adult patients anterior uveitis [i.e. iritis/iridocyclitis] is predominant.54 Data on prevalence of other O-EIMs, such as episcleritis/scleritis or rarer conditions such as orbital myositis, are not available, and only data from case reports are presented. O-EIMs can affect both CD and UC patients, yet our meta-analysis showed that children with CD are at increased risk of O-EIMs as compared withchildren with other paediatric IBD, with an odds ratio of 2.70. No significant study heterogeneity was detected yet, given the paucity of information available, we had to consider together in the analysis studies on EIMs at diagnosis and during the follow-up. Nevertheless, the evaluated outcome [prevalence of O-EIMs] was uniform, and there are no data from either paediatric or adult studies suggesting that timing of data collection may bias prevalence among different IBD subtypes [CD vs UC vs IBD-U]. Hence we can assume that including both types of studies [at diagnosis vs during follow up] did not affect the relative risk analysis. In adult patients, O-EIMs are often considered to be more frequent in CD as compared with UC55; however, data from studies on adult patients are conflicting, with only some studies reporting a significantly increased prevalence of O-EIMs in CD patients, whereas in others the difference appears to be non-significant.1,3,56,57 Data on timing of O-EIMs in children are also scarce. Greuter et al.17 reported a median time of 7 years after IBD diagnosis for uveitis onset, although substantial variability was observed. Occurrence of O-EIMs before gastrointestinal symptoms onset is also possible, even though in a minority of patients; O-EIMs that have been reported to precede intestinal disease include uveitis and orbital myositis. Results from the largest study [Jose et al., 200912] indicate that the prevalence of uveitis increases with time [incidence rate: 0.18 cases per 100 patient-years]. Herzog et al.26 reported no difference for uveitis rates according to age at IBD diagnosis when patients were evaluated after 10 years, possibly indicating that age at IBD onset does not influence uveitis risk per se. Very little data are available also for correlation of O-EIMs with intestinal disease activity. Although uveitis is classically considered to be unrelated to intestinal disease activity, some studies on adult patients actually found a significant correlation with disease activity in patients with CD [but not those with UC].1 Few studies specified concurrent treatments in IBD patients, which may possibly have an effect on the risk of O-EIMs during follow-up. Dotson et al.15 reported a protective effect of immunomodulators and anti-TNF on the overall risk of EIMs in their cohort, yet no data were available for O-EIMs. Systemic immunomodulatory treatments could possibly reduce the risk of inflammatory O-EIMs, but this relationship may not be straightforward. In fact, Greuter et al.17 reported a good response of uveitis to anti-TNF antibodies in two out of three patients, yet the same authors detected uveitis during anti-TNF treatment in two other patients. We did not find evidence of a difference in prevalence of O-EIMs according to patients’ ethnicity. No study provided information on patients’ ethnicity as related to O-EIMs, yet among prevalence studies several world regions were actually included [North America, Western Europe, Turkey, Saudi Arabia, South Korea] and no difference in overall prevalence was observed. Jose et al.12 reported no significant association for patients’ ethnicity with overall EIMs prevalence, but no specific data were available for O-EIMS. Another study, by Eidelwein et al., compared EIMs prevalence between White and African American children in North America.58 This study, however, could not be included in the prevalence analysis because it did not show exact figures of the condition, stating only that uveitis prevalence was ‘less than 3%’ in both groups of patients. Contacted authors also could not provide further information. Nonetheless, no difference in overall EIMs prevalence was reported. Similarly, White et al. found no difference in overall EIMs prevalence in African American children with IBD as compared with other ethnic groups; however, subanalysis of different types of EIMs was not performed, nor could contacted authors provide further information.59 Remarkably, data from adult patients seem to suggest that prevalence of uveitis may be higher in African American CD patients as compared with other ethnic groups.60–62 The recognition of subclinical uveitis by slit lamp examination in screening evaluation in small samples of asymptomatic children with IBD raises concerns about under-diagnosis of a potentially invalidating condition. Three studies [Daum et al., 197927; Hofley et al. 1993;28 Rychwalski et al. 199729] showed a significantly increased prevalence of subclinical uveitis [4.1–23.1%] compared with that reported in cohort populations. It may be worth noting that these studies were performed more than 20 years ago [between 1979 and 1997], before the introduction of biologic anti-tumour necrosis factor alpha agents and the wider use of immune modulators, which allow better control of both gastrointestinal manifestations and EIMs.63,64 The more recent report by Naviglio et al.,23 while confirming the existence of subclinical uveitis in children with IBD, indicated a lower prevalence [1.06%], in line with the prevalence from cohort studies. In all these studies, asymptomatic uveitis was anterior, confirming this as the most common type of uveitis associated with IBD in children, even though other types of uveitis [e.g. intermediate uveitis] are also possible.47 Asymptomatic uveitis did not seem to correlate with intestinal disease activity. Interestingly, some clinical characteristics recurred among patients with asymptomatic uveitis: they were more commonly adolescent males with CD and with colonic involvement [13/14 patients]. This may confirm that CD patients are at increased risk of O-EIMs. Recent data have suggested that eye-specific autoreactive T cells may be activated in the gut from an antigen-dependent cross-reaction on commensal microbiota.65 Abnormal gut permeability in CD and increased density of microbiota in the colon could explain the increased risk of O-EIMs in these patients. However, the low number of cases does not allow us to draw a general conclusion nor to identify other significant characteristics. Clinical implications of asymptomatic uveitis are unclear. In fact, most cases were diagnosed as mild uveitis, and both Daum et al.27 and Naviglio et al.23 reported spontaneous resolution of ocular inflammation without specific treatments, suggesting that asymptomatic uveitis in children with IBD may be transient and self-limiting. Remarkably, no studies detected evidence of ocular complications from previous unrecognised uveitis, suggesting that this type of ocular manifestation may not be aggressive nor lead to complications, at least in children with IBD. This is in sharp contrast with asymptomatic uveitis associated with other paediatric chronic inflammatory disorders, such as juvenile idiopathic arthritis-associated uveitis, which has a high potential for ocular complications and visual impairment.66 Nevertheless, the natural history of asymptomatic uveitis in IBD is poorly known, and therefore definitive conclusions cannot be drawn. Notably, several treatments used in IBD are also effective for uveitis, and thus uveitis may also benefit from systemic treatments used to control intestinal disease. New studies are needed to outline specific phenotype risk and orientate proper follow-up for these patients. Iatrogenic ocular complications, mainly corticosteroid-induced posterior subcapsular cataract and increase of intra-ocular pressure, should also always be considered in children with IBD receiving corticosteroids. Available data on this complication come mostly from the case-control study by Tripathi et al.30 The majority of children [52%] developed either cataract or alteration of intra-ocular pressure; however, this study was performed mainly on children receiving long-term corticosteroid treatment, an eventuality that has now become less frequent, as corticosteroids are considered more as a ‘bridge therapy’. There are few data in medical literature defining timing and dose-related risk of corticosteroid-induced ocular complications in children. It is now well recognised that there is a high inter-individual variability in sensitivity to ocular adverse effects of corticosteroids, with some patients free of ocular complications after years of corticosteroid treatment, whereas in others they may develop rapidly [even as soon as after 2 weeks of treatment].67 Data from adult patients seem to indicate that the overall risk is dose- and time-related, even though a ‘safe dose’ does not seem to exist.68 Notably, corticosteroid-induced complications, especially increased intra-ocular pressure, did respond to dose lowering to less than 10 mg/day of prednisone in the study by Tripathi et al.,30 yet we have not enough data to consider this as a ‘safe’ dose. Therefore, at present, a precise threshold for corticosteroid dose or treatment duration to guide ophthalmological evaluation cannot be clearly defined. In the study by Tripathi et al.,30 the risk of cataract was not correlated to treatment duration or steroid dose, whereas the risk of abnormal intra-ocular pressure was associated to the average dose in the previous 30 days. It may be possible therefore to consider that this is an adequate timing for alterations of intra-ocular pressure to develop. Thus it could be reasonable to suggest that in children in whom systemic corticosteroids are considered for longer periods of time and not as a ‘bridge therapy’ [i.e. in whom tapering and suspension are not programmed after 1 month] an ophthalmological evaluation, including intra-ocular pressure measurement, should be considered after 1 month of therapy. Timing for subsequent evaluations should be decided by the referral ophthalmologist, as there are no data to guide patient management. It is noteworthy that in the study by Tripathi et al.,30 some patients with a previously normal ophthalmological evaluation developed complications after a significant increase in their daily corticosteroid dose, so this should also be taken in consideration in guiding follow-up. All these recommendations are based on low/moderate quality evidence [one case-control study], and therefore their strength should be considered as weak. Patients on very long-term corticosteroid treatment [i.e. treatment continuing for several months/years], however, are at high risk of ocular complications and a strict ocular follow-up should be offered. Available case reports of O-EIMs define a wide array of ocular conditions that have been reported in children with IBD. However, for some of them it is currently not possible to determine whether they were simply coincidental, though similar manifestations have been reported in adult patients. Presenting symptoms varied widely, from mild ocular redness or discomfort to complete loss of vision, highlighting the need not to underestimate ocular complaints in these patients. Reported O-EIMs can be roughly classified into inflammatory and vascular conditions. The first group includes uveitis, episcleritis, orbital myositis/pseudotumour, dacryoadenitis, and optic neuritis. Orbital pseudotumour, which identifies any inflammatory enlargement of intraorbital structural elements,69 despite being a rare condition, was one of the most commonly reported O-EIMs in case reports. Although the clinical manifestations may vary widely, depending on the structures affected, they often included ocular/orbital pain, diplopia, ophthalmoplegia, proptosis, eyelid swelling, and reduced visual acuity. Almost all cases involving an inflammatory O-EIM resolved with treatment, which usually included systemic corticosteroids. Among vascular conditions, we identified reports on retinal artery or vein occlusion and choroidal neovascular membrane; these complications may also share an inflammatory pathogenesis, possibly due to retinal vasculitis, which has been associated with IBD in adults.70 In most cases, vascular conditions resulted in some residual visual impairment despite treatment. Notably, also among case reports there was a preponderance of children with CD [CD/UC = 18/5], thus possibly confirming a greater incidence of O-EIMs in CD patients. In conclusion, available data indicate that prevalence of O-EIMs in children is lower than in adult patients, yet children with CD seem to be at increased risk as compared with other groups of patients. Prevalence of O-EIMs in children may be underestimated in consideration of the possibility of asymptomatic uveitis, which has not been described in adults.71 The significance of this condition, however, is unclear, as all reported cases were mild and self-limiting, with no evidence of ocular complications from underdiagnosis. Nevertheless, data on natural history of this manifestation and long-term follow-up are lacking. It has been recently suggested that annual screening eye examination should be considered in all children with IBD72; however, this is often not performed in clinical practice, nor it is possible to define the cost-benefit ratio of such an approach. Currently, the paucity of data on O-EIMs in children does not allow us to draw clear conclusions on which ophthalmological follow-up should be provided. An option may be to perform ophthalmological evaluation at IBD diagnosis in order to have a baseline reference, but we cannot provide any evidence for this suggestion. On the other hand, we recommend that a low threshold for ophthalmological referral should be maintained in all children with IBD, both at the diagnosis and during follow-up. Available data, in fact, show that most children with O-EIMs presented some ocular signs or symptoms, and therefore ocular complaints should never be dismissed; both health care providers and patients/care givers should be instructed about the increased risk of ocular complications in children with IBD. Since available data indicate a higher incidence of O-EIMs in children with CD, especially if colonic involvement is present, this subset of patients may be considered at higher risk of O-EIMs in clinical practice, but further studies on larger groups of patients are needed. Finally, patients receiving systemic corticosteroids for more than brief periods may probably benefit from ophthalmological evaluations, including intra-ocular pressure measurement. A strict follow-up should be offered in patients receiving long-term corticosteroid treatment, as these children are at increased risk for iatrogenic ocular complications. Funding No funding was received for this work. Conflict of Interest All authors declare no conflict of interests. Author Contributions GO and SN performed literature search and review, wrote the manuscript, and critically revised it. SS, AS, SM, and AV designed the study and critically reviewed the manuscript. All authors approved the manuscript as submitted. References 1. Vavricka SR , Brun L , Ballabeni P , et al. Frequency and risk factors for extraintestinal manifestations in the Swiss inflammatory bowel disease cohort . Am J Gastroenterol 2011 ; 106 : 110 – 9 . Google Scholar CrossRef Search ADS PubMed 2. Isene R , Bernklev T , Høie O , et al. ; EC-IBD Study Group . Extraintestinal manifestations in Crohn’s disease and ulcerative colitis: results from a prospective, population-based European inception cohort . Scand J Gastroenterol 2015 ; 50 : 300 – 5 . Google Scholar CrossRef Search ADS PubMed 3. Karmiris K , Avgerinos A , Tavernaraki A , et al. Prevalence and characteristics of extraintestinal manifestations in a large cohort of Greek patients with inflammatory bowel disease . J Crohns Colitis 2016 ; 10 : 429 – 36 . Google Scholar CrossRef Search ADS PubMed 4. Crohn BB . Ocular lesions complicating ulcerative colitis . Am J Med Sci 1925 ; 169 : 260 – 7 . 5. Hopkins DJ , Horan E , Burton IL , Clamp SE , de Dombal FT , Goligher JC . Ocular disorders in a series of 332 patients with Crohn’s disease . Br J Ophthalmol 1974 ; 58 : 732 – 7 . Google Scholar CrossRef Search ADS PubMed 6. Cury DB , Moss AC . Ocular manifestations in a community-based cohort of patients with inflammatory bowel disease . Inflamm Bowel Dis 2010 ; 16 : 1393 – 6 . Google Scholar CrossRef Search ADS PubMed 7. Yilmaz S , Aydemir E , Maden A , Unsal B . The prevalence of ocular involvement in patients with inflammatory bowel disease . Int J Colorectal Dis 2007 ; 22 : 1027 – 30 . Google Scholar CrossRef Search ADS PubMed 8. Taleban S , Li D , Targan SR , et al. Ocular manifestations in inflammatory bowel disease are associated with other extraintestinal manifestations, gender, and genes implicated in other immune-related traits . J Crohns Colitis 2016 ; 10 : 43 – 9 . Google Scholar CrossRef Search ADS PubMed 9. Felekis T , Katsanos K , Kitsanou M , et al. Spectrum and frequency of ophthalmologic manifestations in patients with inflammatory bowel disease: a prospective single-center study . Inflamm Bowel Dis 2009 ; 15 : 29 – 34 . Google Scholar CrossRef Search ADS PubMed 10. Cassidy J , Kivlin J , Lindsley C , Nocton J ; Section on Rheumatology; Section on Ophthalmology . Ophthalmologic examinations in children with juvenile rheumatoid arthritis . Pediatrics 2006 ; 117 : 1843 – 5 . Google Scholar CrossRef Search ADS PubMed 11. Stroup DF , Berlin JA , Morton SC , et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology [MOOSE] group . JAMA 2000 ; 283 : 2008 – 12 . Google Scholar CrossRef Search ADS PubMed 12. Jose FA , Garnett EA , Vittinghoff E , et al. Development of extraintestinal manifestations in pediatric patients with inflammatory bowel disease . Inflamm Bowel Dis 2009 ; 15 : 63 – 8 . Google Scholar CrossRef Search ADS PubMed 13. Card TR , Langan SM , Chu TP . Extra-gastrointestinal manifestations of inflammatory bowel disease may be less common than previously reported . Dig Dis Sci 2016 ; 61 : 2619 – 26 . Google Scholar CrossRef Search ADS PubMed 14. Castro M , Papadatou B , Baldassare M , et al. Inflammatory bowel disease in children and adolescents in Italy: data from the pediatric national IBD register [1996–2003] . Inflamm Bowel Dis 2008 ; 14 : 1246 – 52 . Google Scholar CrossRef Search ADS PubMed 15. Dotson JL , Hyams JS , Markowitz J , et al. Extraintestinal manifestations of pediatric inflammatory bowel disease and their relation to disease type and severity . J Pediatr Gastroenterol Nutr 2010 ; 51 : 140 – 5 . Google Scholar CrossRef Search ADS PubMed 16. Dimakou K , Pachoula I , Panayotou I , et al. Pediatric inflammatory bowel disease in Greece: 30-years experience of a single center . Ann Gastroenterol 2015 ; 28 : 81 – 6 . Google Scholar PubMed 17. Greuter T , Bertoldo F , Rechner R , et al. ; Swiss IBD Cohort Study Group . Extraintestinal manifestations of pediatric inflammatory bowel disease: prevalence, presentation, and anti-TNF treatment . J Pediatr Gastroenterol Nutr 2017 ; 65 : 200 – 6 . Google Scholar CrossRef Search ADS PubMed 18. Duricova D , Leroyer A , Savoye G , et al. Extra-intestinal manifestations at diagnosis in paediatric- and elderly-onset ulcerative colitis are associated with a more severe disease outcome: a population-based study . J Crohns Colitis 2017 ; 11 : 1326 – 34 . Google Scholar CrossRef Search ADS PubMed 19. Cakir M , Unal F , Dinler G , et al. Inflammatory bowel disease in Turkish children . World J Pediatr 2015 ; 11 : 331 – 7 . Google Scholar CrossRef Search ADS PubMed 20. Gower-Rousseau C , Dauchet L , Vernier-Massouille G , et al. The natural history of pediatric ulcerative colitis: a population-based cohort study . Am J Gastroenterol 2009 ; 104 : 2080 – 8 . Google Scholar CrossRef Search ADS PubMed 21. Martinelli M , Giugliano FP , Russo M , et al. The changing face of pediatric ulcerative colitis . J Pediatr Gastroenterol Nutr 2017 : 1 . Doi: 10.1097/MPG.0000000000001833 . [Epub ahead of print.] 22. Saadah OI . Childhood onset of Crohn disease: experience from a university teaching hospital in Saudi Arabia . Ann Saudi Med 2012 ; 32 : 596 – 602 . Google Scholar CrossRef Search ADS PubMed 23. Naviglio S , Parentin F , Nider S , Rassu N , Martelossi S , Ventura A . Ocular involvement in children with inflammatory bowel disease . Inflamm Bowel Dis 2017 ; 23 : 986 – 90 . Google Scholar CrossRef Search ADS PubMed 24. Lee YA , Chun P , Hwang EH , Mun SW , Lee YJ , Park JH . Clinical features and extraintestinal manifestations of crohn disease in children . Pediatr Gastroenterol Hepatol Nutr 2016 ; 19 : 236 – 42 . Google Scholar CrossRef Search ADS PubMed 25. Aziz DA , Moin M , Majeed A , Sadiq K , Biloo AG . Paediatric inflammatory bowel disease: clinical presentation and disease location . Pak J Med Sci 2017 ; 33 : 793 – 7 . Google Scholar PubMed 26. Herzog D , Fournier N , Buehr P , et al. Age at disease onset of inflammatory bowel disease is associated with later extraintestinal manifestations and complications . Eur J Gastroenterol Hepatol 2018 : 1 . Doi: 10.1097/MEG.0000000000001072 . 27. Daum F , Gould HB , Gold D , et al. Asymptomatic transient uveitis in children with inflammatory bowel disease . Am J Dis Child 1979 ; 133 : 170 – 1 . Google Scholar PubMed 28. Hofley P , Roarty J , McGinnity G , et al. Asymptomatic uveitis in children with chronic inflammatory bowel diseases . J Pediatr Gastroenterol Nutr 1993 ; 17 : 397 – 400 . Google Scholar CrossRef Search ADS PubMed 29. Rychwalski PJ , Cruz OA , Alanis-Lambreton G , Foy TM , Kane RE . Asymptomatic uveitis in young people with inflammatory bowel disease . J AAPOS 1997 ; 1 : 111 – 4 . Google Scholar CrossRef Search ADS PubMed 30. Tripathi RC , Kipp MA , Tripathi BJ , et al. Ocular toxicity of prednisone in pediatric patients with inflammatory bowel disease . Lens Eye Toxic Res 1992 ; 9 : 469 – 82 . Google Scholar PubMed 31. Vayalambrone D , Ivanova T , Misra A . Nonischemic central retinal vein occlusion in an adolescent patient with ulcerative colitis . Case Rep Ophthalmol Med 2011 ; 2011 : 963583 . Google Scholar PubMed 32. Falavarjani KG , Parvaresh MM , Shahraki K , Nekoozadeh S , Amirfarhangi A . Central retinal artery occlusion in Crohn disease . J Am Assoc Pediatr Ophthalmol Strabismus 2012 ; 16 : 392 – 3 . Google Scholar CrossRef Search ADS 33. Lapsia S , Meyer R , Abazari A , Usmani K , Gathungu G . Bilateral central retinal vein occlusion in a patient with ulcerative colitis and antiphospholipid antibody syndrome . J Pediatr Gastroenterol Nutr 2016 ; 62 : e25 – 6 . Google Scholar CrossRef Search ADS PubMed 34. Young RS , Hodes BL , Cruse RP , Koch KL , Garovoy MR . Orbital pseudotumor and Crohn disease . J Pediatr 1981 ; 99 : 250 – 2 . Google Scholar CrossRef Search ADS PubMed 35. Camfield PR , White M , Warner HA , Lythgoe C . Orbital pseudotumor and Crohn disease . J Pediatr 1982 ; 101 : 157 – 8 . Google Scholar CrossRef Search ADS PubMed 36. Weinstein JM , Koch K , Lane S . Orbital pseudotumor in Crohn’s colitis . Ann Ophthalmol 1984 ; 16 : 275 – 8 . Google Scholar PubMed 37. Squires RH Jr , Zwiener RJ , Kennedy RH . Orbital myositis and Crohn’s disease . J Pediatr Gastroenterol Nutr 1992 ; 15 : 448 – 51 . Google Scholar CrossRef Search ADS PubMed 38. Durno CA , Ehrlich R , Taylor R , Buncic JR , Hughes P , Griffiths AM . Keeping an eye on Crohn’s disease: orbital myositis as the presenting symptom . Can J Gastroenterol 1997 ; 11 : 497 – 500 . Google Scholar CrossRef Search ADS PubMed 39. Tan JHT , Arkachaisri T , Das L , Chu HP . Orbital pseudotumour as a presentation of paediatric ulcerative colitis . Singapore Med J 2014 ; 55 : 169 – 71 . Google Scholar CrossRef Search ADS 40. Vargason CW , Mawn LA . Orbital myositis as both a presenting and associated extraintestinal sign of Crohn’s disease . Ophthal Plast Reconstr Surg 2015 ; 33 ( Suppl 1): S158– 60 . Google Scholar CrossRef Search ADS 41. Thomas BJ , Emanuelli AA , Berrocal AM . Unilateral choroidal neovascular membrane as a herald lesion for Crohn’s disease . Ophthalmic Surg Lasers Imaging Retina 2014 ; 45 : 62 – 5 . Google Scholar CrossRef Search ADS PubMed 42. Greninger DA , Yoon MK , Bloomer MM , Keyser R , Kersten RC . Extraintestinal Crohn disease causing bilateral nasolacrimal duct obstruction . Ophthal Plast Reconstr Surg 2012 ; 28 : e55 – 6 . Google Scholar CrossRef Search ADS PubMed 43. Rafiei N , Tabandeh H , Hirschbein M . Bilateral dacroadenitis associated with acute Crohn’s disease . Eye [Lond] 2006 ; 20 : 1372 – 3 . Google Scholar PubMed 44. Mrugacz M , Sredzińska-Kita D , Cyrta-Jarocka E , Bakunowicz-Lazarczyk A . Dry eye syndrome and cataract as ocular manifestations of Crohn’s disease . Klin Oczna 2005 ; 107 : 509 – 10 . Google Scholar PubMed 45. Paroli MP , Spinucci G , Bruscolini A , La Cava M , Abicca I . Uveitis preceding Crohn’s disease by 8 years . Int Ophthalmol 2011 ; 31 : 413 – 5 . Google Scholar CrossRef Search ADS PubMed 46. Girardin M , Waschke KA , Seidman EG . A case of acute loss of vision as the presenting symptom of Crohn’s disease . Nat Clin Pract Gastroenterol Hepatol 2007 ; 4 : 695 – 8 . Google Scholar CrossRef Search ADS PubMed 47. Symeonidis C , Matsou A , Tzetzi D , Dermenoudi M , Brazitikos P , Mataftsi A . Amblyopia due to intermediate uveitis as the presenting symptom of Crohn’s disease in a 6-year-old boy . J AAPOS 2017 ; 21 : 512– 4 . Google Scholar CrossRef Search ADS PubMed 48. Read RW , Weiss AH , Sherry DD . Episcleritis in childhood . Ophthalmology 1999 ; 106 : 2377 – 9 . Google Scholar CrossRef Search ADS PubMed 49. Fasci-Spurio F , Thompson A , Madill S , Koay P , Mansfield D , Satsangi J . Sight-threatening keratopathy complicating anti-TNF therapy in Crohn’s disease: a case report . Inflamm Bowel Dis 2014 ; 20 : E2 – 3 . Google Scholar CrossRef Search ADS PubMed 50. Seo JK , Yeon KM , Chi JG . Inflammatory bowel disease in children - clinical, endoscopic, radiologic and histopathologic investigation . J Korean Med Sci 1992 ; 7 : 221 – 35 . Google Scholar CrossRef Search ADS PubMed 51. Blase WP , Knox DL , Green WR . Granulomatous conjunctivitis in a patient with Crohn’s disease . Br J Ophthalmol 1984 ; 68 : 901 – 3 . Google Scholar CrossRef Search ADS PubMed 52. Barabino AV , Gandullia P , Calvi A , Vignola S , Arrigo S , Marco RD . Sudden blindness in a child with Crohn’s disease . World J Gastroenterol 2011 ; 17 : 4344 – 6 . Google Scholar CrossRef Search ADS PubMed 53. Shoari M , Katz BJ . Recurrent neuroretinitis in an adolescent with ulcerative colitis . J Neuroophthalmol 2005 ; 25 : 286 – 8 . Google Scholar CrossRef Search ADS PubMed 54. Taylor SR , McCluskey P , Lightman S . The ocular manifestations of inflammatory bowel disease . Curr Opin Ophthalmol 2006 ; 17 : 538 – 44 . Google Scholar CrossRef Search ADS PubMed 55. Vavricka SR , Schoepfer A , Scharl M , Lakatos PL , Navarini A , Rogler G . Extraintestinal manifestations of inflammatory bowel disease . Inflamm Bowel Dis 2015 ; 21 : 1982 – 92 . Google Scholar CrossRef Search ADS PubMed 56. Zippi M , Corrado C , Pica R , et al. Extraintestinal manifestations in a large series of Italian inflammatory bowel disease patients . World J Gastroenterol 2014 ; 20 : 17463 – 7 . Google Scholar CrossRef Search ADS PubMed 57. Greenstein AJ , Janowitz HD , Sachar DB . The extraintestinal complications of Crohn’s disease and ulcerative colitis: a study of 700 patients . Medicine [Baltimore] 1976 ; 55 : 401 – 12 . Google Scholar CrossRef Search ADS PubMed 58. Eidelwein AP , Thompson R , Fiorino K , Abadom V , Oliva-Hemker M . Disease presentation and clinical course in black and white children with inflammatory bowel disease . J Pediatr Gastroenterol Nutr 2007 ; 44 : 555 – 60 . Google Scholar CrossRef Search ADS PubMed 59. White JM , O’Connor S , Winter HS , et al. Inflammatory bowel disease in African American children compared with other racial/ethnic groups in a multicenter registry . Clin Gastroenterol Hepatol 2008 ; 6 : 1361 – 9 . Google Scholar CrossRef Search ADS PubMed 60. Basu D , Lopez I , Kulkarni A , Sellin JH . Impact of race and ethnicity on inflammatory bowel disease . Am J Gastroenterol 2005 ; 100 : 2254 – 61 . Google Scholar CrossRef Search ADS PubMed 61. Nguyen GC , Torres EA , Regueiro M , et al. Inflammatory bowel disease characteristics among African Americans, Hispanics, and non-Hispanic Whites: characterization of a large North American cohort . Am J Gastroenterol 2006 ; 101 : 1012 – 23 . Google Scholar CrossRef Search ADS PubMed 62. Hou JK , El-Serag H , Thirumurthi S . Distribution and manifestations of inflammatory bowel disease in Asians, Hispanics, and African Americans: a systematic review . Am J Gastroenterol 2009 ; 104 : 2100 – 9 . Google Scholar CrossRef Search ADS PubMed 63. Löfberg R , Louis EV , Reinisch W , et al. Adalimumab produces clinical remission and reduces extraintestinal manifestations in Crohn’s disease: results from CARE . Inflamm Bowel Dis 2012 ; 18 : 1 – 9 . Google Scholar CrossRef Search ADS PubMed 64. Peyrin-Biroulet L , Van Assche G , Gómez-Ulloa D , et al. Systematic review of tumor necrosis factor antagonists in extraintestinal manifestations in inflammatory bowel disease . Clin Gastroenterol Hepatol 2017 ; 15 : 25 – 36.e27 . Google Scholar CrossRef Search ADS PubMed 65. Horai R , Zárate-Bladés CR , Dillenburg-Pilla P , et al. Microbiota-dependent activation of an autoreactive T cell receptor provokes autoimmunity in an immunologically privileged site . Immunity 2015 ; 43 : 343 – 53 . Google Scholar CrossRef Search ADS PubMed 66. Heiligenhaus A , Niewerth M , Ganser G , Heinz C , Minden K ; German Uveitis in Childhood Study Group . Prevalence and complications of uveitis in juvenile idiopathic arthritis in a population-based nation-wide study in Germany: suggested modification of the current screening guidelines . Rheumatology [Oxford] 2007 ; 46 : 1015 – 9 . Google Scholar CrossRef Search ADS PubMed 67. Malgarinos G , Giannakoulopoulou E , Mastrangelis A , et al. Cataract development as a complication of corticosteroid treatment in a young patient with ulcerative colitis . Ann Gastroenterol 2006 ; 19 : 358 – 9 . 68. Skalka HW , Prchal JT . Effect of corticosteroids on cataract formation . Arch Ophthalmol 1980 ; 98 : 1773 – 7 . Google Scholar CrossRef Search ADS PubMed 69. Katsanos A , Asproudis I , Katsanos KH , Dastiridou AI , Aspiotis M , Tsianos EV . Orbital and optic nerve complications of inflammatory bowel disease . J Crohns Colitis 2013 ; 7 : 683 – 93 . Google Scholar CrossRef Search ADS PubMed 70. Matsuo T , Yamaoka A . Retinal vasculitis revealed by fluorescein angiography in patients with inflammatory bowel disease . Jpn J Ophthalmol 1998 ; 42 : 398 – 400 . Google Scholar CrossRef Search ADS PubMed 71. Verbraak FD , Schreinemachers MC , Tiller A , van Deventer SJ , de Smet MD . Prevalence of subclinical anterior uveitis in adult patients with inflammatory bowel disease . Br J Ophthalmol 2001 ; 85 : 219 – 21 . Google Scholar CrossRef Search ADS PubMed 72. DeFilippis EM , Sockolow R , Barfield E . Health care maintenance for the pediatric patient with inflammatory bowel disease . Pediatrics 2016 ; 138 : e20151971 . Google Scholar CrossRef Search ADS PubMed Copyright © 2018 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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Journal of Crohn's and ColitisOxford University Press

Published: Mar 6, 2018

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